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Publisher: John Wiley and Sons   (Total: 1589 journals)

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Showing 1 - 200 of 1589 Journals sorted alphabetically
Abacus     Hybrid Journal   (Followers: 12, SJR: 0.48, h-index: 22)
About Campus     Hybrid Journal   (Followers: 5)
Academic Emergency Medicine     Hybrid Journal   (Followers: 65, SJR: 1.385, h-index: 91)
Accounting & Finance     Hybrid Journal   (Followers: 48, SJR: 0.547, h-index: 30)
ACEP NOW     Free   (Followers: 1)
Acta Anaesthesiologica Scandinavica     Hybrid Journal   (Followers: 53, SJR: 1.02, h-index: 88)
Acta Archaeologica     Hybrid Journal   (Followers: 168, SJR: 0.101, h-index: 9)
Acta Geologica Sinica (English Edition)     Hybrid Journal   (Followers: 3, SJR: 0.552, h-index: 41)
Acta Neurologica Scandinavica     Hybrid Journal   (Followers: 5, SJR: 1.203, h-index: 74)
Acta Obstetricia et Gynecologica Scandinavica     Hybrid Journal   (Followers: 15, SJR: 1.197, h-index: 81)
Acta Ophthalmologica     Hybrid Journal   (Followers: 6, SJR: 0.112, h-index: 1)
Acta Paediatrica     Hybrid Journal   (Followers: 56, SJR: 0.794, h-index: 88)
Acta Physiologica     Hybrid Journal   (Followers: 6, SJR: 1.69, h-index: 88)
Acta Polymerica     Hybrid Journal   (Followers: 9)
Acta Psychiatrica Scandinavica     Hybrid Journal   (Followers: 37, SJR: 2.518, h-index: 113)
Acta Zoologica     Hybrid Journal   (Followers: 7, SJR: 0.459, h-index: 29)
Acute Medicine & Surgery     Hybrid Journal   (Followers: 5)
Addiction     Hybrid Journal   (Followers: 36, SJR: 2.086, h-index: 143)
Addiction Biology     Hybrid Journal   (Followers: 14, SJR: 2.091, h-index: 57)
Adultspan J.     Hybrid Journal   (SJR: 0.127, h-index: 4)
Advanced Energy Materials     Hybrid Journal   (Followers: 26, SJR: 6.411, h-index: 86)
Advanced Engineering Materials     Hybrid Journal   (Followers: 26, SJR: 0.81, h-index: 81)
Advanced Functional Materials     Hybrid Journal   (Followers: 51, SJR: 5.21, h-index: 203)
Advanced Healthcare Materials     Hybrid Journal   (Followers: 14, SJR: 0.232, h-index: 7)
Advanced Materials     Hybrid Journal   (Followers: 295, SJR: 9.021, h-index: 345)
Advanced Materials Interfaces     Hybrid Journal   (Followers: 6, SJR: 1.177, h-index: 10)
Advanced Optical Materials     Hybrid Journal   (Followers: 7, SJR: 2.488, h-index: 21)
Advanced Science     Open Access   (Followers: 5)
Advanced Synthesis & Catalysis     Hybrid Journal   (Followers: 17, SJR: 2.729, h-index: 121)
Advances in Polymer Technology     Hybrid Journal   (Followers: 13, SJR: 0.344, h-index: 31)
Africa Confidential     Hybrid Journal   (Followers: 21)
Africa Research Bulletin: Economic, Financial and Technical Series     Hybrid Journal   (Followers: 13)
Africa Research Bulletin: Political, Social and Cultural Series     Hybrid Journal   (Followers: 11)
African Development Review     Hybrid Journal   (Followers: 33, SJR: 0.275, h-index: 17)
African J. of Ecology     Hybrid Journal   (Followers: 16, SJR: 0.477, h-index: 39)
Aggressive Behavior     Hybrid Journal   (Followers: 15, SJR: 1.391, h-index: 66)
Aging Cell     Open Access   (Followers: 11, SJR: 4.374, h-index: 95)
Agribusiness : an Intl. J.     Hybrid Journal   (Followers: 3, SJR: 0.627, h-index: 14)
Agricultural and Forest Entomology     Hybrid Journal   (Followers: 16, SJR: 0.925, h-index: 43)
Agricultural Economics     Hybrid Journal   (Followers: 45, SJR: 1.099, h-index: 51)
AIChE J.     Hybrid Journal   (Followers: 32, SJR: 1.122, h-index: 120)
Alcoholism and Drug Abuse Weekly     Hybrid Journal   (Followers: 7)
Alcoholism Clinical and Experimental Research     Hybrid Journal   (Followers: 7, SJR: 1.416, h-index: 125)
Alimentary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 33, SJR: 2.833, h-index: 138)
Alimentary Pharmacology & Therapeutics Symposium Series     Hybrid Journal   (Followers: 3)
Allergy     Hybrid Journal   (Followers: 51, SJR: 3.048, h-index: 129)
Alternatives to the High Cost of Litigation     Hybrid Journal   (Followers: 3)
American Anthropologist     Hybrid Journal   (Followers: 152, SJR: 0.951, h-index: 61)
American Business Law J.     Hybrid Journal   (Followers: 24, SJR: 0.205, h-index: 17)
American Ethnologist     Hybrid Journal   (Followers: 93, SJR: 2.325, h-index: 51)
American J. of Economics and Sociology     Hybrid Journal   (Followers: 29, SJR: 0.211, h-index: 26)
American J. of Hematology     Hybrid Journal   (Followers: 35, SJR: 1.761, h-index: 77)
American J. of Human Biology     Hybrid Journal   (Followers: 13, SJR: 1.018, h-index: 58)
American J. of Industrial Medicine     Hybrid Journal   (Followers: 16, SJR: 0.993, h-index: 85)
American J. of Medical Genetics Part A     Hybrid Journal   (Followers: 16, SJR: 1.115, h-index: 61)
American J. of Medical Genetics Part B: Neuropsychiatric Genetics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 107)
American J. of Medical Genetics Part C: Seminars in Medical Genetics     Partially Free   (Followers: 6, SJR: 2.315, h-index: 79)
American J. of Physical Anthropology     Hybrid Journal   (Followers: 37, SJR: 1.41, h-index: 88)
American J. of Political Science     Hybrid Journal   (Followers: 290, SJR: 5.101, h-index: 114)
American J. of Primatology     Hybrid Journal   (Followers: 16, SJR: 1.197, h-index: 63)
American J. of Reproductive Immunology     Hybrid Journal   (Followers: 3, SJR: 1.347, h-index: 75)
American J. of Transplantation     Hybrid Journal   (Followers: 18, SJR: 2.792, h-index: 140)
American J. on Addictions     Hybrid Journal   (Followers: 9, SJR: 0.843, h-index: 57)
Anaesthesia     Hybrid Journal   (Followers: 138, SJR: 1.404, h-index: 88)
Analyses of Social Issues and Public Policy     Hybrid Journal   (Followers: 9, SJR: 0.397, h-index: 18)
Analytic Philosophy     Hybrid Journal   (Followers: 20)
Anatomia, Histologia, Embryologia: J. of Veterinary Medicine Series C     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 27)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1, SJR: 0.633, h-index: 24)
Andrologia     Hybrid Journal   (Followers: 2, SJR: 0.528, h-index: 45)
Andrology     Hybrid Journal   (Followers: 2, SJR: 0.979, h-index: 14)
Angewandte Chemie     Hybrid Journal   (Followers: 179)
Angewandte Chemie Intl. Edition     Hybrid Journal   (Followers: 229, SJR: 6.229, h-index: 397)
Animal Conservation     Hybrid Journal   (Followers: 41, SJR: 1.576, h-index: 62)
Animal Genetics     Hybrid Journal   (Followers: 8, SJR: 0.957, h-index: 67)
Animal Science J.     Hybrid Journal   (Followers: 6, SJR: 0.569, h-index: 24)
Annalen der Physik     Hybrid Journal   (Followers: 5, SJR: 1.46, h-index: 40)
Annals of Anthropological Practice     Partially Free   (Followers: 2, SJR: 0.187, h-index: 5)
Annals of Applied Biology     Hybrid Journal   (Followers: 7, SJR: 0.816, h-index: 56)
Annals of Clinical and Translational Neurology     Open Access   (Followers: 1)
Annals of Human Genetics     Hybrid Journal   (Followers: 9, SJR: 1.191, h-index: 67)
Annals of Neurology     Hybrid Journal   (Followers: 48, SJR: 5.584, h-index: 241)
Annals of Noninvasive Electrocardiology     Hybrid Journal   (Followers: 1, SJR: 0.531, h-index: 38)
Annals of Public and Cooperative Economics     Hybrid Journal   (Followers: 8, SJR: 0.336, h-index: 23)
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5, SJR: 2.389, h-index: 189)
Annual Bulletin of Historical Literature     Hybrid Journal   (Followers: 13)
Annual Review of Information Science and Technology     Hybrid Journal   (Followers: 14)
Anthropology & Education Quarterly     Hybrid Journal   (Followers: 25, SJR: 0.72, h-index: 31)
Anthropology & Humanism     Hybrid Journal   (Followers: 17, SJR: 0.137, h-index: 3)
Anthropology News     Hybrid Journal   (Followers: 15)
Anthropology of Consciousness     Hybrid Journal   (Followers: 11, SJR: 0.172, h-index: 5)
Anthropology of Work Review     Hybrid Journal   (Followers: 11, SJR: 0.256, h-index: 5)
Anthropology Today     Hybrid Journal   (Followers: 91, SJR: 0.545, h-index: 15)
Antipode     Hybrid Journal   (Followers: 50, SJR: 2.212, h-index: 69)
Anz J. of Surgery     Hybrid Journal   (Followers: 8, SJR: 0.432, h-index: 59)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apmis     Hybrid Journal   (Followers: 1, SJR: 0.855, h-index: 73)
Applied Cognitive Psychology     Hybrid Journal   (Followers: 70, SJR: 0.754, h-index: 69)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7, SJR: 0.632, h-index: 58)
Applied Psychology     Hybrid Journal   (Followers: 209, SJR: 1.023, h-index: 64)
Applied Psychology: Health and Well-Being     Hybrid Journal   (Followers: 50, SJR: 0.868, h-index: 13)
Applied Stochastic Models in Business and Industry     Hybrid Journal   (Followers: 5, SJR: 0.613, h-index: 24)
Aquaculture Nutrition     Hybrid Journal   (Followers: 14, SJR: 1.025, h-index: 55)
Aquaculture Research     Hybrid Journal   (Followers: 32, SJR: 0.807, h-index: 60)
Aquatic Conservation Marine and Freshwater Ecosystems     Hybrid Journal   (Followers: 36, SJR: 1.047, h-index: 57)
Arabian Archaeology and Epigraphy     Hybrid Journal   (Followers: 11, SJR: 0.453, h-index: 11)
Archaeological Prospection     Hybrid Journal   (Followers: 12, SJR: 0.922, h-index: 21)
Archaeology in Oceania     Hybrid Journal   (Followers: 13, SJR: 0.745, h-index: 18)
Archaeometry     Hybrid Journal   (Followers: 29, SJR: 0.809, h-index: 48)
Archeological Papers of The American Anthropological Association     Hybrid Journal   (Followers: 15, SJR: 0.156, h-index: 2)
Architectural Design     Hybrid Journal   (Followers: 26, SJR: 0.261, h-index: 9)
Archiv der Pharmazie     Hybrid Journal   (Followers: 3, SJR: 0.628, h-index: 43)
Archives of Drug Information     Hybrid Journal   (Followers: 5)
Archives of Insect Biochemistry and Physiology     Hybrid Journal   (SJR: 0.768, h-index: 54)
Area     Hybrid Journal   (Followers: 13, SJR: 0.938, h-index: 57)
Art History     Hybrid Journal   (Followers: 274, SJR: 0.153, h-index: 13)
Arthritis & Rheumatology     Hybrid Journal   (Followers: 54, SJR: 1.984, h-index: 20)
Arthritis Care & Research     Hybrid Journal   (Followers: 27, SJR: 2.256, h-index: 114)
Artificial Organs     Hybrid Journal   (Followers: 1, SJR: 0.872, h-index: 60)
ASHE Higher Education Reports     Hybrid Journal   (Followers: 15)
Asia & the Pacific Policy Studies     Open Access   (Followers: 16)
Asia Pacific J. of Human Resources     Hybrid Journal   (Followers: 326, SJR: 0.494, h-index: 19)
Asia Pacific Viewpoint     Hybrid Journal   (Followers: 1, SJR: 0.616, h-index: 26)
Asia-Pacific J. of Chemical Engineering     Hybrid Journal   (Followers: 8, SJR: 0.345, h-index: 20)
Asia-pacific J. of Clinical Oncology     Hybrid Journal   (Followers: 6, SJR: 0.554, h-index: 14)
Asia-Pacific J. of Financial Studies     Hybrid Journal   (SJR: 0.241, h-index: 7)
Asia-Pacific Psychiatry     Hybrid Journal   (Followers: 4, SJR: 0.377, h-index: 7)
Asian Economic J.     Hybrid Journal   (Followers: 8, SJR: 0.234, h-index: 21)
Asian Economic Policy Review     Hybrid Journal   (Followers: 4, SJR: 0.196, h-index: 12)
Asian J. of Control     Hybrid Journal   (SJR: 0.862, h-index: 34)
Asian J. of Endoscopic Surgery     Hybrid Journal   (Followers: 1, SJR: 0.394, h-index: 7)
Asian J. of Organic Chemistry     Hybrid Journal   (Followers: 6, SJR: 1.443, h-index: 19)
Asian J. of Social Psychology     Hybrid Journal   (Followers: 5, SJR: 0.665, h-index: 37)
Asian Politics and Policy     Hybrid Journal   (Followers: 12, SJR: 0.207, h-index: 7)
Asian Social Work and Policy Review     Hybrid Journal   (Followers: 5, SJR: 0.318, h-index: 5)
Asian-pacific Economic Literature     Hybrid Journal   (Followers: 5, SJR: 0.168, h-index: 15)
Assessment Update     Hybrid Journal   (Followers: 4)
Astronomische Nachrichten     Hybrid Journal   (Followers: 3, SJR: 0.701, h-index: 40)
Atmospheric Science Letters     Open Access   (Followers: 29, SJR: 1.332, h-index: 27)
Austral Ecology     Hybrid Journal   (Followers: 15, SJR: 1.095, h-index: 66)
Austral Entomology     Hybrid Journal   (Followers: 9, SJR: 0.524, h-index: 28)
Australasian J. of Dermatology     Hybrid Journal   (Followers: 8, SJR: 0.714, h-index: 40)
Australasian J. On Ageing     Hybrid Journal   (Followers: 6, SJR: 0.39, h-index: 22)
Australian & New Zealand J. of Statistics     Hybrid Journal   (Followers: 14, SJR: 0.275, h-index: 28)
Australian Accounting Review     Hybrid Journal   (Followers: 3, SJR: 0.709, h-index: 14)
Australian and New Zealand J. of Family Therapy (ANZJFT)     Hybrid Journal   (Followers: 3, SJR: 0.382, h-index: 12)
Australian and New Zealand J. of Obstetrics and Gynaecology     Hybrid Journal   (Followers: 47, SJR: 0.814, h-index: 49)
Australian and New Zealand J. of Public Health     Hybrid Journal   (Followers: 11, SJR: 0.82, h-index: 62)
Australian Dental J.     Hybrid Journal   (Followers: 6, SJR: 0.482, h-index: 46)
Australian Economic History Review     Hybrid Journal   (Followers: 6, SJR: 0.171, h-index: 12)
Australian Economic Papers     Hybrid Journal   (Followers: 31, SJR: 0.23, h-index: 9)
Australian Economic Review     Hybrid Journal   (Followers: 6, SJR: 0.357, h-index: 21)
Australian Endodontic J.     Hybrid Journal   (Followers: 3, SJR: 0.513, h-index: 24)
Australian J. of Agricultural and Resource Economics     Hybrid Journal   (Followers: 3, SJR: 0.765, h-index: 36)
Australian J. of Grape and Wine Research     Hybrid Journal   (Followers: 5, SJR: 0.879, h-index: 56)
Australian J. of Politics & History     Hybrid Journal   (Followers: 15, SJR: 0.203, h-index: 14)
Australian J. of Psychology     Hybrid Journal   (Followers: 18, SJR: 0.384, h-index: 30)
Australian J. of Public Administration     Hybrid Journal   (Followers: 419, SJR: 0.418, h-index: 29)
Australian J. of Rural Health     Hybrid Journal   (Followers: 5, SJR: 0.43, h-index: 34)
Australian Occupational Therapy J.     Hybrid Journal   (Followers: 72, SJR: 0.59, h-index: 29)
Australian Psychologist     Hybrid Journal   (Followers: 12, SJR: 0.331, h-index: 31)
Australian Veterinary J.     Hybrid Journal   (Followers: 23, SJR: 0.459, h-index: 45)
Autism Research     Hybrid Journal   (Followers: 36, SJR: 2.126, h-index: 39)
Autonomic & Autacoid Pharmacology     Hybrid Journal   (SJR: 0.371, h-index: 29)
Banks in Insurance Report     Hybrid Journal   (Followers: 1)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 11, SJR: 0.539, h-index: 70)
Basic and Applied Pathology     Open Access   (Followers: 2, SJR: 0.113, h-index: 4)
Basin Research     Hybrid Journal   (Followers: 5, SJR: 1.54, h-index: 60)
Bauphysik     Hybrid Journal   (Followers: 2, SJR: 0.194, h-index: 5)
Bauregelliste A, Bauregelliste B Und Liste C     Hybrid Journal  
Bautechnik     Hybrid Journal   (Followers: 1, SJR: 0.321, h-index: 11)
Behavioral Interventions     Hybrid Journal   (Followers: 9, SJR: 0.297, h-index: 23)
Behavioral Sciences & the Law     Hybrid Journal   (Followers: 24, SJR: 0.736, h-index: 57)
Berichte Zur Wissenschaftsgeschichte     Hybrid Journal   (Followers: 10, SJR: 0.11, h-index: 5)
Beton- und Stahlbetonbau     Hybrid Journal   (Followers: 2, SJR: 0.493, h-index: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6, SJR: 0.311, h-index: 26)
Bioelectromagnetics     Hybrid Journal   (Followers: 1, SJR: 0.568, h-index: 64)
Bioengineering & Translational Medicine     Open Access  
BioEssays     Hybrid Journal   (Followers: 10, SJR: 3.104, h-index: 155)
Bioethics     Hybrid Journal   (Followers: 14, SJR: 0.686, h-index: 39)
Biofuels, Bioproducts and Biorefining     Hybrid Journal   (Followers: 1, SJR: 1.725, h-index: 56)
Biological J. of the Linnean Society     Hybrid Journal   (Followers: 16, SJR: 1.172, h-index: 90)
Biological Reviews     Hybrid Journal   (Followers: 5, SJR: 6.469, h-index: 114)
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 41, SJR: 0.12, h-index: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9, SJR: 1.812, h-index: 69)
Biomedical Chromatography     Hybrid Journal   (Followers: 6, SJR: 0.572, h-index: 49)
Biometrical J.     Hybrid Journal   (Followers: 5, SJR: 0.784, h-index: 44)
Biometrics     Hybrid Journal   (Followers: 37, SJR: 1.906, h-index: 96)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 10, SJR: 0.715, h-index: 44)
Biopolymers     Hybrid Journal   (Followers: 18, SJR: 1.199, h-index: 104)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 44, SJR: 0.415, h-index: 55)
Biotechnology and Bioengineering     Hybrid Journal   (Followers: 152, SJR: 1.633, h-index: 146)
Biotechnology J.     Hybrid Journal   (Followers: 14, SJR: 1.185, h-index: 51)
Biotechnology Progress     Hybrid Journal   (Followers: 39, SJR: 0.736, h-index: 101)
Biotropica     Hybrid Journal   (Followers: 20, SJR: 1.374, h-index: 71)
Bipolar Disorders     Hybrid Journal   (Followers: 9, SJR: 2.592, h-index: 100)
Birth     Hybrid Journal   (Followers: 38, SJR: 0.763, h-index: 64)
Birth Defects Research Part A : Clinical and Molecular Teratology     Hybrid Journal   (Followers: 2, SJR: 0.727, h-index: 77)
Birth Defects Research Part B: Developmental and Reproductive Toxicology     Hybrid Journal   (Followers: 7, SJR: 0.468, h-index: 47)
Birth Defects Research Part C : Embryo Today : Reviews     Hybrid Journal   (SJR: 1.513, h-index: 55)
BJOG : An Intl. J. of Obstetrics and Gynaecology     Partially Free   (Followers: 247, SJR: 2.083, h-index: 125)

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Journal Cover Acta Physiologica
  [SJR: 1.69]   [H-I: 88]   [6 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1748-1708 - ISSN (Online) 1748-1716
   Published by John Wiley and Sons Homepage  [1589 journals]
  • NO, CO, and H2S: what about gasotransmitters in fish and amphibian
    • Authors: Sandra Imbrogno; Mariacristina Filice, Maria Carmela Cerra, Alfonsina Gattuso
      Abstract: The gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), long considered only toxicant, are produced in vivo during the catabolism of common biological molecules, and are crucial for a large variety of physiological processes. Mounting evidence is emerging that in poikilotherm vertebrates, as in mammals, they modulate the basal performance of the heart and the response to stress challenges. In this review, we will focus on teleost fish and amphibians to highlight the evolutionary importance in vertebrates of the cardiac control elicited by NO, CO and H2S, and the conservation of the intracellular cascades they activate. Although many gaps are still present due to discontinuous information, we will use examples obtained by studies from our and other laboratories to illustrate the complexity of the mechanisms that, by involving gasotransmitters, allows beat-to-beat, short-, medium- and long-term cardiac homeostasis. By presenting the latest data, we will also provide a framework in which the peculiar morpho-functional arrangement of the teleost and amphibian heart can be considered as a reference tool to decipher cardiac regulatory networks which are difficult to explore by using more conventional vertebrates, such as mammals.This article is protected by copyright. All rights reserved
      PubDate: 2018-01-16T16:50:27.831218-05:
      DOI: 10.1111/apha.13035
  • Light and Darkness
    • Authors: Pontus B. Persson; Anja B. Persson
      Abstract: Life on earth follows cyclic processes, of which the diurnal cycle of the sun rising and setting is one of the most evident. The rotation of the earth dictates the waking and resting cycles of numerous life forms on earth. While we can safely assume that our earliest human ancestors will have recognized, sometimes feared or even worshipped the cyclic nature of Life on Earth, the knowledge that almost “all multicellular organisms, including humans, utilize a similar mechanism to control circadian rhythms” [1], has only very recently warranted a Nobel Prize in Physiology/Medicine.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-16T09:10:21.250438-05:
      DOI: 10.1111/apha.13036
  • Specific labelling of myonuclei by an antibody against Pericentriolar
           material 1 (PCM1) on skeletal muscle tissue sections
    • Authors: I. M. Winje; M. Bengtsen, E. Eftestøl, I. Juvkam, J. C. Bruusgaard, K. Gundersen
      Abstract: AimSkeletal muscle is a heterogeneous tissue containing several different cell types and only about 40 – 50% of the cell nuclei within the tissue belong to myofibres. Existing technology, attempting to distinguish myonuclei from other nuclei at the light microscopy level, has led to controversies in our understanding of the basic cell biology of muscle plasticity. The present study aims at demonstrating that an antibody against the protein Pericentriolar material 1 (PCM1) can be used to reliably identify myonuclei on histological cross sections from humans, mice and rats.MethodsCryo-sections were labelled with a polyclonal antibody against PCM1. The specificity of the labelling for myonuclei was verified by using 3D reconstructions of confocal z-stacks triple labelled for DNA, dystrophin and PCM1, and by co-localization with nuclear mCherry driven by the muscle specific Actin Alpha 1 promoter after viral transduction.ResultsThe PCM1 antibody specifically labelled all myonuclei, and myonuclei only, in cryo-sections of muscles from rats, mice and men. Nuclei in other cell types including satellite cells were not labelled. Both normal muscles and hypertrophic muscles after synergist ablation were investigated.ConclusionPCM1 can be used as a specific histological marker for myonuclei in skeletal muscle tissue without relying on counter staining of other structures or cumbersome and subjective analysis of nuclear positioning.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-13T04:45:20.539674-05:
      DOI: 10.1111/apha.13034
  • Cyclosporine A induces Endothelin-Converting Enzyme (ECE)-1: Studies
           in-vivo and in-vitro
    • Authors: Samuel N. Heyman; Zaid Abassi, Christian Rosenberger, Hiba Yaseen, Galia Skarjinski, Ahuva Shina, Susanne Mathia, Natalia Krits, Mogher Khamaisi
      Abstract: AimCyclosporine A (CsA) induces renal vasoconstriction and hypoxia and enhances the expression of endothelin-1 (ET-1) pro-hormone (pre-pro ET-1), plausibly leading to a feed-forward loop of renal vasoconstriction, hypoxia, and enhanced synthesis of the potent vasoconstrictor ET-1. Endothelin converting enzyme (ECE)-1 cleaves big endothelin to generate endothelin (ET)-1 and is up-regulated by hypoxia via hypoxia-inducible factor (HIF). We hypothesized that in addition to the direct induction of ET-1 synthesis, CsA might also intensify renal ECE-1expression, thus contributing to enhanced ET-1 synthesis following CsA.MethodsCsA was administered to Sprague Dawley rats (120 mg/kg/SC) for 4 days and renal HIF and ECE-1 expression were assessed with western blots and immunostaining. Human umbilical vein endothelial cells (HUVEC) and proximal tubular cell line (HK-2) were subjected to CsA and ECE-1 induction was evaluated using real-time mRNA PCR and western blots.ResultsCsA intensified renal parenchymal ECE-1 expression in the rat kidney, particularly in distal nephron segments, along with renal hypoxia (detected by pimonidazole adducts) and HIF expression, in line with our recent observations showing episodic hypoxia in mice subjected to CsA. Furthermore, in cultured normoxic HUVEC and HK-2 cells, CsA dose-dependently induced both pre-pro-ET-1 and ECE-1 mRNA and protein expression, with enhanced ET-1generation.ConclusionsCsA induces ECE-1 via both hypoxic and non-hypoxic pathways. ECE-1 may contribute to increased renal ET-1 generation following CsA, participating in a feed-forward loop of renal parenchymal hypoxia and ET synthesis.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-13T04:35:18.526921-05:
      DOI: 10.1111/apha.13033
  • Mitochondrial respiratory capacity remains stable despite a comprehensive
           and sustained increase in insulin sensitivity in obese patients undergoing
           gastric bypass surgery
    • Authors: Michael T Lund; Steen Larsen, Merethe Hansen, Julie Courraud, Andrea K. Floyd, Mikael Støckel, Jørn W. Helge, Flemming Dela
      Abstract: AimIt has been proposed, but not yet demonstrated by convincing evidence in published articles, that insulin resistance and mitochondrial respiratory function are causally-related physiological phenomena. Here, we tested the prediction that weight loss induced increase in insulin sensitivity will correlate with a corresponding change in mitochondrial respiratory capacity over the same time period.MethodsInsulin sensitivity was evaluated using the hyperinsulinaemic-euglycemic clamp technique and skeletal muscle mitochondrial respiratory capacity was evaluated by high-resolution respirometry in 26 patients with obesity. Each experiment was performed ~2 months and 1-2 weeks before, and ~4 and ~19 months after Roux-en-Y Gastric Bypass (RYGB) surgery.ResultsA substantial weight loss was observed in all patients, and insulin sensitivity increased in all patients over the twenty-one month time period of the study. In contrast, skeletal muscle mitochondrial respiratory capacity, intrinsic mitochondrial respiratory capacity and mitochondrial content remained unchanged over the same time period.ConclusionsAmong obese patients with and without type 2 diabetes undergoing RYGB surgery, intrinsic mitochondrial respiratory capacity in skeletal muscle is not correlated with insulin sensitivity before or after the surgical intervention. Mitochondrial respiratory function may not be germane to the pathophysiology and/or etiology of obesity and/or type 2 diabetes.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-13T04:25:19.60064-05:0
      DOI: 10.1111/apha.13032
  • Issue Information
    • PubDate: 2018-01-12T03:48:09.434404-05:
      DOI: 10.1111/apha.12950
  • Effects of chronic hypoxia on diaphragm function in deer mice native to
           high altitude
    • Authors: Neal J. Dawson; Sulayman A. Lyons, Danielle A. Henry, Graham R. Scott
      Abstract: AimWe examined the effects of chronic hypoxia on diaphragm function in high- and low-altitude populations of Peromyscus mice.MethodsDeer mice (P. maniculatus) native to high altitude and congeneric mice native to low altitude (P. leucopus) were born and raised in captivity to adulthood, and were acclimated to normoxia or hypobaric hypoxia (12 or 9 kPa, simulating hypoxia at 4300 m and 7000 m) for 6-8 weeks. We then measured indices of mitochondrial respiration capacity, force production, and fatigue resistance in the diaphragm.ResultsMitochondrial respiratory capacities (assessed using permeabilized fibres with single or multiple inputs to the electron transport system), citrate synthase activity (a marker of mitochondrial volume), twitch force production, and muscle fatigue resistance increased after exposure to chronic hypoxia in both populations. These changes were not well explained by variation in the fibre-type composition of the muscle. However, there were several differences in diaphragm function in high-altitude mice compared to low-altitude mice. Exposure to a deeper level of hypoxia (9 kPa vs 12 kPa) was needed to elicit increases in mitochondrial respiration rates in highlanders. Chronic hypoxia did not increase the emission of reactive oxygen species from permeabilized fibres in highlanders, in contrast to the pronounced increases that occurred in lowlanders. In general, the diaphragm of high-altitude mice had greater capillary length densities, produced less force in response to stimulation, and had shorter relaxation times. The latter was associated with higher activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity in the diaphragm of high-altitude mice.ConclusionOverall, our work suggests that exposure to chronic hypoxia increases the capacities for mitochondrial respiration, force production, and fatigue resistance of the diaphragm. However, many of these effects are opposed by evolved changes in diaphragm function in high-altitude natives, such that highlanders in chronic hypoxia maintain similar diaphragm function to lowlanders in sea level conditions.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-09T06:15:21.25767-05:0
      DOI: 10.1111/apha.13030
  • Post-factual Gender in Science debate
    • Authors: P. B. Persson
      Abstract: Gender issues come up regularly in science too. Yet here, imbalance - if not outright discrimination - is often anticipated when
      PubDate: 2018-01-07T22:40:18.790848-05:
      DOI: 10.1111/apha.13029
  • Increased temperature accelerates glycogen synthesis and delays fatigue in
           isolated mouse muscle during repeated contractions
    • Authors: Ester Hanya; Abram Katz
      Abstract: AimElevated glycogen content in muscle delays fatigue during exercise. We examined if increasing muscle temperature during recovery from exercise affects glycogen synthesis and muscle performance during a subsequent bout of exercise.MethodsIsolated mouse extensor digitorum longus muscles were stimulated electrically to perform repeated tetanic contractions until force decreased to 40% of initial at 25°C. Thereafter muscles recovered for 120 min at 25°C (control), 120 min at 35°C, or 60 min at 35°C followed by 60 min at 25°C. After recovery, muscles were again stimulated to fatigue at 25°C.ResultsIn the control group, the number of contractions in the second run was slightly less than during the first run (92±5%). Following recovery for 120 min at 35°C the number of contractions were similar to the first run (98±6%). Allowing recovery for 120 min at 35°C in the presence of the antioxidant N-acetylcysteine also did not alter the number of contractions in the second run (98±3%). However, recovery for 60 min at 35°C followed by 60 min at 25°C resulted in an increase in the number of contractions during the second run (110±2%, P
      PubDate: 2018-01-03T06:51:22.670935-05:
      DOI: 10.1111/apha.13027
  • Platelet responses to pharmacological and physiological interventions in
           middle-aged men with different habitual physical activity levels
    • Authors: M. H Lundberg Slingsby; L Gliemann, M Thrane, N Rytter, J Egelund, M. V Chan, P. C Armstrong, T. D Warner, Y Hellsten
      Abstract: The current guidelines following an acute coronary syndrome recommend dual anti-platelet therapy (aspirin plus a P2Y12 antagonist) alongside lifestyle modifications, including more regular physical activity. It is currently unknown if regular exercise affects the pharmacology of dual anti-platelet therapy.AimTo explore how exercise-induced improvements in vascular and platelet function affect the efficacy of dual anti-platelet therapy, in a cross-sectional study of men with different physical activity level (training status).Methods42 healthy, normal-weight, middle-aged men were divided into 3 groups; untrained, moderately- and well-trained. Their platelet reactivity (agonist-induced %aggregation) was investigated in platelet rich plasma at rest and after inhibition with aspirin and ticagrelor and/or prostacyclin and nitric oxide added to the blood in vitro, and after physiological tests of vascular function; passive movement of the leg, flow-mediated dilation and one-leg knee-extensor exercise. Vascular function of the femoral artery (changes in arterial blood flow) was assessed by ultrasound doppler.ResultsPlatelets from the well-trained subjects had lower basal reactivity, a higher sensitivity to the anti-aggregatory effects of prostacyclin and were more potently inhibited by dual anti-platelet therapy compared to the untrained subjects. The moderately- and well-trained subjects had a superior vascular function compared to untrained subjects and their platelets were more inhibited by the passive movement, flow-mediated dilation and one-leg knee extensor exercise.ConclusionA habitually active lifestyle leads to an increased platelet sensitivity to pharmacological and physiological platelet inhibitors. We suggest that physical activity habits (training status) should be considered when personalising and optimizing anti-thrombotic treatment strategies.This article is protected by copyright. All rights reserved.
      PubDate: 2018-01-03T06:51:20.843444-05:
      DOI: 10.1111/apha.13028
  • Body clocks: time for the Nobel Prize
    • Authors: Charna Dibner; Ueli Schibler
      Abstract: Already in 1729 Jean-Jacques d'Ortous de Mairan, a French astronomer, noticed that the mimosa plants in his backyard opened and closed their leaves at similar times during the day. Intriguingly, these daily cycles of leaf movements persisted in plants kept in nearly constant darkness, and de Mairan thus concluded that they must be driven by endogenous clocks rather than environmental light-dark cycles. In the meantime self-sustained circadian oscillators have been found in nearly all light-sensitive organisms from cyanobacteria to mammals. In the latter they influence most aspects of physiology and behaviour and thus play essential roles in health and disease. Molecular research on these biological timekeepers has been initiated in the 1980ies in the fruit fly Drosophila melanogaster by Jeffrey Hall, Michael Rosbash, and Michael Young, and their discovery of the first clock genes has been honoured with the 2017 Nobel Prize in Physiology or Medicine. As elaborated below, the Drosophila and mammalian clocks are very similar, and the work on Drosophila clocks has been pivotal in the identification of mammalian clock genes and in their functional analysis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-28T01:40:32.494617-05:
      DOI: 10.1111/apha.13024
  • Epigenetic changes mediating transition to chronic kidney disease: hypoxic
    • Authors: Tetsuhiro Tanaka
      Abstract: Underlying mechanisms accounting for the transition of AKI to CKD have been eagerly sought. Candidates so far include nephron loss, inflammation, endothelial injury with vascular rarefaction and cell cycle arrest in epithelial cells. Among them, hypoxia is increasingly recognized as a common pathway mediating transition from AKI to CKD 2.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-28T01:40:26.01825-05:0
      DOI: 10.1111/apha.13023
  • Uniaxial strain of cultured mouse and rat cardiomyocyte strands slows
           conduction more when its axis is parallel to impulse propagation than when
           it is perpendicular
    • Authors: Andrea Buccarello; Michela Azzarito, Frédéric Michoud, Stéphanie P. Lacour, Jan P. Kucera
      Abstract: AimCardiac tissue deformation can modify tissue resistance, membrane capacitance and ion currents, and hence cause arrhythmogenic slow conduction. Our aim was to investigate whether uniaxial strain causes different changes in conduction velocity (θ) when the principal strain axis is parallel vs. perpendicular to impulse propagation.MethodsCardiomyocyte strands were cultured on stretchable custom microelectrode arrays and θ was determined during steady-state pacing. Uniaxial strain (5%) with principal axis parallel (orthodromic) or perpendicular (paradromic) to propagation was applied for 1 min and controlled by imaging a grid of markers. The results were analysed in terms of cable theory.ResultsBoth types of strain induced immediate changes of θ upon application and release. In material coordinates, orthodromic strain decreased θ significantly more (p
      PubDate: 2017-12-28T01:36:58.57291-05:0
      DOI: 10.1111/apha.13026
  • A sticky wicket: overexpression of integrin alpha 11 is sufficient for
           cardiac fibrosis
    • Authors: Andrew Leask
      Abstract: Increased mechanical loading in the microenvironment is linked to pathologies including fibrosis, a group of connective tissue disorders characterized by increased production of scar tissue that culminates in organ failure and, often, death. Cells sense surrounding stiffness via cell surface receptors called integrins, which stimulate downstream signaling molecules including focal adhesion kinase to cause further overproduction and remodeling of connective tissue. Thus increased mechanical loading (i.e., stiff connective tissue) perpetuates the fibrotic phenotype.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-28T01:05:31.750725-05:
      DOI: 10.1111/apha.13025
  • Cell-specific resetting of mouse islet cellular clocks by glucagon,
           glucagon-like peptide 1, and somatostatin
    • Authors: Volodymyr Petrenko; Charna Dibner
      Abstract: AimMolecular clocks, operative in pancreatic islet cells, represent an intrinsic mechanism regulating intracellular metabolism and hormone secretion. Glucagon, somatostatin and glucagon-like peptide 1 (GLP-1) are essential coordinators of islet physiology. Here, we assess the synchronizing capacity of glucagon, somatostatin and GLP-1 on pancreatic α- and β-cell circadian clocks.MethodsTriple transgenic mice, expressing a circadian PER2::luciferase (luc) reporter combined with α- and β-cell specific fluorescent reporters were employed. Isolated pancreatic islets and FACS-separated α- and β-cells were synchronized with glucagon, somatostatin analogue or GLP-1 mimetics, with subsequent real-time PER2::luc bioluminescence recording. Gene expression of Gcgr, Sstr2, Sstr3, and Glp1r in islet cells was assessed by RNA sequencing and RT-qPCR.ResultsGlucagon and GLP-1 mimetics (liraglutide and exenatide) induced high-amplitude rhythmic expression of the PER2::luc reporter in β-cells, but not in α-cells, while the somatostatin analogue octreotide generated a significant phase shift between α- and β-cells. Enrichment of Gcgr and Glp1r transcripts was detected in β-cells compared to their α-cell counterparts. The synchronizing effect of glucagon was dose-dependent, and mediated by the adenylate cyclase signaling cascade, as it was diminished by adenylate cyclase inhibitor.ConclusionWe conclude that proglucagon-derived peptides and somatostatin exhibit receptor-mediated cell-specific synchronizing effects for mouse α- and β-cell oscillators. Differential islet cell clock modulation by glucagon and somatostatin may represent a physiological mechanism underlying paracrine regulation of rhythmic glucagon and insulin secretion. The reported here strong synchronizing properties of GLP-1 mimetics, widely used for treatment of type 2 diabetes, are of high clinical relevance.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-22T07:30:46.498873-05:
      DOI: 10.1111/apha.13021
  • Record submission of well over 600 manuscript in 2017
    • Authors: P. B. Persson
      Abstract: In the face of dramatically increasing numbers of profit oriented journals, most of them open access,1, 2 it is a particular pleasure that Acta Physiologica receives more and more submissions by the year. As you know, Acta Physiologica provides the authors with the choice of open access or free to publish. On top, all color figures are free and we supply less favored regions of the world with free access to Acta Physiologica. It seems that it is possible to provide open access and free to publish options, while providing free subscriptions for those scientists in need.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-21T08:36:13.778192-05:
      DOI: 10.1111/apha.13022
  • Stress affects expression of the clock gene Bmal1 in the suprachiasmatic
           nucleus of neonatal rats via glucocorticoid-dependent mechanism
    • Authors: Lucie Olejníková; Lenka Polidarová, Alena Sumová
      Abstract: AimThe reactivity of the circadian clock in the suprachiasmatic nuclei (SCN) to stressful stimuli has been controversial but most studies have confirmed the resilience of the SCN to stress. We tested the hypothesis that during a critical period shortly after birth, the developing SCN clock is affected by glucocorticoids.MethodsMothers of two rat strains with different sensitivities to stress, i.e., Wistar rats and spontaneously hypertensive rats (SHR), and their pups were exposed to stressful stimuli every day from delivery, and clock gene expression profiles were detected in the 4-day-old pups’ SCN. Levels of glucocorticoids in plasma were measured by LC-MS/MS. The glucocorticoid receptors antagonist mifepristone was administered to pups to block the effect of the glucocorticoids.ResultsThe glucocorticoid receptors were detected at the mRNA and protein levels in the SCN of 4-day-old pups. The exposure of mothers to stressful stimuli elevated their plasma glucocorticoid levels. In Wistar rat pups, combination of daily maternal stress with their manipulation increased the plasma glucocorticoid levels and shifted the Bmal1 rhythm in the SCN which was completely blocked by mifepristone. In contrast, in SHR pups, maternal stress on its own caused phase shift of the Bmal1 expression rhythm in the SCN but the effect was mediated via glucocorticoid-independent mechanism. The Per1 and Per2 expression profiles remained phase-locked to the light/dark cycle.ConclusionThe results demonstrate that the SCN is sensitive to stressful stimuli early after birth in pups maintained under light/dark conditions and the effect is mediated via glucocorticoid-dependent pathways.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-20T09:55:46.0996-05:00
      DOI: 10.1111/apha.13020
  • Tendinous tissue properties after short and long-term functional overload:
    • Authors: G.J Massey; T.G Balshaw, T.M Maden-Wilkinson, J.P Folland
      Abstract: AimThe potential for tendinous tissues to adapt to functional overload, especially after several years of exposure to heavy resistance training is largely unexplored. This study compared the morphological and mechanical characteristics of the patellar tendon and knee-extensor tendon-aponeurosis complex between young men exposed to long-term (4 years; n=16), short-term (12 weeks; n=15) and no (untrained controls; n=39) functional overload in the form of heavy resistance training.MethodsPatellar tendon cross-sectional area, vastus-lateralis aponeurosis area and quadriceps femoris volume, plus patellar tendon stiffness and Young's modulus, and tendon-aponeurosis complex stiffness, were quantified with MRI, dynamometry and ultrasonography.ResultsAs expected long-term trained had greater muscle strength and volume (+58% and +56% vs untrained, both P
      PubDate: 2017-12-18T12:50:23.481632-05:
      DOI: 10.1111/apha.13019
  • Regulatory mechanisms of microRNA sorting into extracellular vesicles
    • Authors: Andreas Zietzer; Nikos Werner, Felix Jansen
      Abstract: Coronary artery disease is the most important cause of mortality worldwide. In the last decades, key mechanisms of atherosclerosis and plaque formation have been described. It is commonly accepted, that continuous damage of endothelial cells by oxidative stress causes endothelial apoptosis and dysfunction, which mark the beginning of atherosclerotic plaque formation.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-18T12:40:25.149251-05:
      DOI: 10.1111/apha.13018
  • Novel concepts in sleep regulation
    • Authors: Henna-Kaisa Wigren; Tarja Porkka-Heiskanen
      Abstract: Knowledge regarding the cellular mechanisms of sleep regulation is accumulating rapidly. In addition to neurons, also non-neuronal brain cells (astrocytes and microglia) are emerging as potential players. New techniques, particularly optogenetics and designed receptors activated by artificial ligands (DREADD) have provided also sleep research with important additional tools to study the effect of either silencing or activating specific neuronal groups/neuronal networks by opening or shutting ion channels on cells. The advantages of these strategies are the possibility to genetically target specific cell populations and the possibility to either activate or inhibit them with inducing light signal into the brain. Studies probing circuits of NREM and REM sleep regulation, as well as their role in memory consolidation have been conducted recently. In addition, fundamentally new thoughts and potential mechanisms have been introduced to the field.The role of non-neuronal tissues in the regulation of many brain functions has become evident. These non-neuronal cells, particularly astrocytes, integrate large number of neurons, and it has been suggested that one of their functions is to integrate the (neural) activity in larger brain areas – a feature that is one of the prominent features of also the state of sleep.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-18T12:40:23.563931-05:
      DOI: 10.1111/apha.13017
  • Molecular mechanisms and physiological relevance of RGK proteins in the
    • Authors: U. Meza; D. Beqollari, R.A. Bannister
      Abstract: The primary route of Ca2+ entry into cardiac myocytes is via 1,4-dihydropyridine-sensitive, voltage-gated L-type Ca2+ channels. Ca2+ influx through these channels influences duration of action potential and engages excitation-contraction (EC) coupling in both the atria and the myocardium. Members of the RGK (Rad, Rem, Rem2, and Gem/Kir) family of small GTP binding proteins are potent, endogenously-expressed inhibitors of cardiac L-type channels. Although much work has focused on the molecular mechanisms by which RGK proteins inhibit the CaV1.2 and CaV1.3 L-type channel isoforms that expressed in the heart, their impact on greater cardiac function is only beginning to come into focus. In this review, we summarize recent findings regarding the influence of RGK proteins on normal cardiac physiology and the pathological consequences of aberrant RGK activity.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-13T18:19:19.948125-05:
      DOI: 10.1111/apha.13016
  • Glucocorticoid receptor activation is associated with increased resistance
           to heat-induced hyperthermia and injury
    • Authors: Yifan Chen; Tianzheng Yu
      Abstract: AimAnti-inflammatory mediators likely play a key role in maintaining thermal homeostasis and providing protection against heat stress. The aim of this study was to investigate the association between activation of the glucocorticoid receptor (GR) and resistance to heat-induced hyperthermia and injury.MethodsEffects of heat exposure on core body temperature, muscle GR phosphorylation status and subcellular expression were examined in control mice and thermal acclimation (TA)-exposed mice. In addition, effects of TA and corticosterone on C2C12 mouse myoblast viability and subcellular GR were assessed during heat exposure.ResultsPhosphorylated, nuclear, and mitochondrial GR levels were significantly higher in the gastrocnemius muscles of mice with mild hyperthermia (tolerant), compared to mice with severe hyperthermia (intolerant) during a heat exposure test. Similar changes were found in mice after TA, compared to non-TA exposed controls. Additional groups of TA and non-TA exposed mice underwent a heat exposure test. TA mice presented a significantly lower hyperthermic response during heat exposure than non-TA exposed control. C2C12 cells exposed to TA incubation had higher viability against heat shock, and showed higher GR levels in their mitochondria and nuclei detected by western blot analysis and fluorescence microscopy, compared to cells exposed to normal incubation. Furthermore, pre-incubation with 0.1 μM corticosterone increased C2C12 cell viability during heat exposure and, mitochondrial and nuclear GR expression.ConclusionThe results of these in vivo and in vitro studies suggest that GR activation is associated with increased resistance against heat-induced hyperthermia and injury.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-12T03:10:57.604549-05:
      DOI: 10.1111/apha.13015
  • Fishing for histamine H3 receptor functions
    • Authors: Helmut Haas
      Abstract: Puttonen et al. (this issue) report behavioral features and abnormalities of zebrafish lacking the histamine H3 receptor, which regulates the release of several neurotransmitters, including GABA, glutamate, histamine, serotonin, noradrenaline and dopamine1. Despite normal morphological development, mutant larvae show faster locomotor adaptation to sudden darkness than control larvae, whereas there are no differences in basic locomotor activity during daytime and night. Zebrafish sleep, defined by immobility for a period of longer than 1 min, is normal in hrh3 KO larvae.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-12T03:08:44.371308-05:
      DOI: 10.1111/apha.13014
  • Hydrochlorothiazide and acute urinary acidification: The ‘voltage
           hypothesis’ of ENaC-dependent H+ secretion refuted
    • Authors: Niklas Ayasse; Pauline I. A. de Bruijn, Peder Berg, Mads V. Sørensen, Jens Leipziger
      Abstract: AimThe ‘voltage hypothesis’ of H+ secretion states that urinary acidification following increased Na+ delivery to the collecting duct (CD) is ENaC-dependent leading to transepithelial voltage-dependent increase in H+ secretion. We recently showed that furosemide acidifies the urine independently of ENaC activity. If the voltage hypothesis holds, hydrochlorothiazide (HCT) must acidify the urine. We here tested the acute effect of HCT on urine pH under normal and high ENaC expression.MethodsMice subjected to a control or a low-Na+ diet were anesthetized and infused (0.5 ml h−1) with saline. Catheterization of the urinary bladder allowed real-time measurement of diuresis and urine pH. Mice received either HCT (1mg ml−1) or vehicle. Urinary Na+ and K+ excretions were determined by flame photometry. ENaC expression levels were measured by semi-quantitive Western Blotting.Results(1) HCT increased diuresis and natriuresis in both diet groups. (2) K+ excretion rates increased after HCT administration from 18.6±1.3 to 31.7±2.5 μmol h−1 in the control diet group and from 23.0±1.3 to 48.7±3.0 μmol h−1 in the low-Na+ diet group. (3) Mice fed a low-Na+ diet showed a marked upregulation of ENaC. (4) Importantly, no acute changes in urine pH were observed after the administration of HCT in either group.ConclusionAcute administration of HCT has no effect on urine pH. Similarly, substantial functional and molecular up-regulation of ENaC did not cause HCT to acutely change urine pH. Thus, an increased Na+ load to the CD does not alter urine pH. This supports our previous finding and likely falsifies the voltage hypothesis of H+ secretion.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-11T02:30:00.122513-05:
      DOI: 10.1111/apha.13013
  • Cellular models for beta cell function and diabetes gene therapy
    • Authors: Alastair D Green; Srividya Vasu, Peter R Flatt
      Abstract: Diabetes is characterised by the destruction and/or relative dysfunction of insulin secreting beta-cells in the pancreatic islets of Langerhans. Consequently, considerable effort has been made to understand the physiological processes governing insulin production and secretion in these cells, and to elucidate the mechanisms involved in their deterioration in the pathogenesis of diabetes. To date, considerable research has exploited clonal beta-cell lines derived from rodent insulinomas. Such cell-lines have proven to be a great asset in diabetes research, in vitro drug testing, and studies of beta-cell physiology; and provide a sustainable, and in many cases, more practical alternative to the use of animals or primary tissue. However, selection of the most appropriate rodent beta cell-line is often challenging and no single cell line entirely recapitulates the properties of human beta-cells. The generation of stable human beta-cell lines would provide a much more suitable model for studies of human beta-cell physiology and pathology, and could potentially be used as a readily available source of implantable insulin-releasing tissue for cell-based therapies of diabetes. In this review, we discuss the history, development, functional characteristics and use of available clonal rodent beta-cell lines, as well as reflecting on recent advances in the generation of human derived beta-cell lines, their use in research studies, and their potential for cell-therapy of diabetes.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-11T02:19:29.558898-05:
      DOI: 10.1111/apha.13012
  • Does mean arterial blood pressure scale with body mass in mammals' –
           effects of measurement of blood pressure
    • Authors: Christian Bo Poulsen; Tobias Wang, Kasper Assersen, Nina Kerting Iversen, Mads Damkjær
      Abstract: For at least the last 30 years it has been discussed whether mean arterial blood pressure (MAP) is independent of body mass or whether it increases in accordance with the vertical height between the heart and the brain. The debate has centered on the most appropriate mathematical models for analysing allometric scaling and phylogenetic relationships, there has been preciously little focus on evaluating the validity of underlying physiological data. Currently, the two most comprehensive scaling analyses are based on data from 47 species of mammals, based on 114 references. We reviewed all available references to determine under which physiological conditions MAP had been recorded. In 44 (38.6%) of the cited references MAP was measured in anaesthetized animals. Data from conscious animals were reported in 59 (51.8%) of references, of these 3 (2.6%) were radiotelemetric studies. In 5 species, data were reported from both anaesthetized and conscious animals, the mean difference in MAP between these settings was 20 ± 29 mmHg. From a literature search we identified MAP measurements performed by radiotelemetry in 11 of the 47 species included in the meta-analyses. A Bland-Altman analysis showed a bias of 1 mmHg with 95% confidence interval (from -35 to 36 mmHg); i.e. the limits of agreement between radiotelemetric studies and studies in restrained animals was double the supposed difference in MAP between the mouse and elephant. In conclusion, the existing literature does not provide evidence for either a positive or neutral scaling of arterial pressure to body mass across taxa.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-05T21:40:56.272768-05:
      DOI: 10.1111/apha.13010
  • Sympathetic nerve activity and neuro-inflammation: Who is in the driver's
    • Authors: Snigdha Mukerjee; Eric Lazartigues
      Abstract: The current study by Fan et al.[1] in this issue of Acta Physiologica entitled ‘Orexin A increases sympathetic nerve activity through promoting expression of proinflammatory cytokines in Sprague-Dawley rats’ sheds some light on the potential signaling pathways leading to cardiovascular activation with regards to increased sympathetic activity and neuro-inflammation and provide an interesting model for future work testing the neuro-inflammation-driven hypertension hypothesis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-12-05T21:40:53.360874-05:
      DOI: 10.1111/apha.13011
  • High-intensity interval training improves insulin sensitivity in older
    • Authors: D Søgaard; M T Lund, C M Scheuer, M S Dehlbæk, S G Dideriksen, C V Abildskov, K K Christensen, T L Dohlmann, S Larsen, A H Vigelsø, F Dela, J W Helge
      Abstract: AimMetabolic health may deteriorate with age as a result of altered body composition and decreased physical activity. Endurance exercise is known to counter these changes delaying or even preventing onset of metabolic diseases. High-intensity interval training (HIIT) is a time efficient alternative to regular endurance exercise and the aim of this study is to investigate the metabolic benefit of HIIT in older subjects.Methods22 sedentary male (n=11) and female (n=11) subjects aged 63 ± 1 years performed HIIT training three times/week for six weeks on a bicycle ergometer. Each HIIT session consisted of five 1 minute intervals interspersed by 1½ minute rest. Prior to the first and after the last HIIT session whole-body insulin sensitivity, measured by hyperinsulinaemic-euglycaemic clamp, plasma lipid levels, HbA1c, glycaemic parameters, body composition and maximal oxygen uptake were assessed. Muscle biopsies were obtained wherefrom content of glycogen and proteins involved in muscle glucose handling were determined.ResultsInsulin sensitivity (p=0.011) and maximal oxygen uptake increased (p
      PubDate: 2017-12-02T02:50:21.122326-05:
      DOI: 10.1111/apha.13009
  • Suppression of circadian secretion of glucagon-like peptide-1 by the
           saturated fatty acid, palmitate
    • Authors: A. Martchenko; R.H. Oh, S.E. Wheeler, P. Gurges, J. A. Chalmers, P. L. Brubaker
      Abstract: AimGlucagon-like peptide-1 is an incretin hormone secreted by the intestinal L-cell with a circadian rhythm that parallels expression of the core clock gene, Bmal1. Although feeding rats a high-fat/high-sucrose Western diet impairs rhythmic glucagon-like peptide-1 release, the mechanisms underlying this effect remain unclear. Therefore, the aim of the present study was to determine the pathway(s) by which the saturated fat, palmitate, a major component of the Western diet, impairs circadian glucagon-like peptide-1 secretion.MethodsMurine mGLUTag L-cells were synchronized and the effects of palmitate pre-treatment on gene expression and glucagon-like peptide-1 secretion were determined, in addition to metabolite quantification, mitochondrial function analysis, and enzyme inhibition and activation assays. Glucagon-like peptide-1 secretion was also analyzed in ileal crypt cultures from control and Bmal1 knockout mice.ResultsPre-treatment with palmitate dampened Bmal1 mRNA and protein expression and glucagon-like peptide-1 secretion at 8 but not 20 hours after cell synchronization (p
      PubDate: 2017-11-29T11:40:31.229801-05:
      DOI: 10.1111/apha.13007
  • Cooperative role of the GLP-1 receptor and β3-adrenergic-mediated
           signaling on fat mass reduction through the down-regulation of
           PKA/AKT/AMPK signaling in the adipose tissue and muscle of rats
    • Authors: Juan Decara; Patricia Rivera, Sergio Arrabal, Antonio Vargas, Antonia Serrano, Francisco Javier Pavón, Carlos Dieguez, Rubén Nogueiras, Fernando Rodríguez de Fonseca, Juan Suárez
      Abstract: AimTo explore the cooperation of GLP-1 receptor and β3-adrenergic receptor-mediated signaling in the control of fat mass/feeding behavior by studying the effects of a combined therapy composed of the GLP-1R agonist liraglutide and the β3-AR agonist CL316243.MethodsThe study included the analysis of key mechanisms regulating lipid/cholesterol metabolism, and thermogenesis in brown (BAT) and epididymal white (eWAT) adipose tissues, abdominal muscle and liver of male rats.ResultsCL316243 (1 mg kg−1) and liraglutide (100 μg kg−1) co-administration over 6 days potentiated an overall negative energy balance (reduction in food intake, body weight gain, fat/non-fat mass ratio, liver fat content, and circulating levels of NEFAs, triglycerides, VLDL-cholesterol and leptin). These effects were accompanied by increased plasma levels of insulin and IL6. We also observed increased gene expression of uncoupling proteins regulating thermogenesis in BAT/eWAT (Ucp1) and muscle (Ucp2/3). Expression of transcription factor and enzymes involved either in de novo lipogenesis (Chrebp, Acaca, Fasn, Scd1, Insig1, Srebp1) or in fatty acid β-oxidation (Cpt1b) was enhanced in eWAT and/or muscle but decreased in BAT. Pparα and Pparγ, essentials in lipid flux/storage, were decreased in BAT/eWAT but increased in the muscle and liver. Cholesterol synthesis regulators (Insig2, Srebp2, Hmgcr) were particularly over-expressed in muscle. These GLP-1R/β3-AR-induced metabolic effects were associated with the down-regulation of cAMP-dependent signaling pathways (PKA/AKT/AMPK).ConclusionsCombined activation of GLP-1 and β3-adrenergic receptors potentiate changes in peripheral pathways regulating lipid/cholesterol metabolism in a tissue-specific manner that favors a switch in energy availability/expenditure and may be useful for obesity treatment.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-28T04:58:03.123992-05:
      DOI: 10.1111/apha.13008
  • The interstitium conducts extrarenal storage of sodium and represents a
           third compartment essential for extracellular volume and blood pressure
    • Authors: Helge Wiig; Friedrich C Luft, Jens Titze
      Abstract: The role of salt in the pathogenesis of arterial hypertension is not well understood. According to the current understanding, the central mechanism for blood pressure regulation relies on classical studies linking blood pressure and Na+ balance, placing the kidney at the very centre of long-term blood pressure regulation. To maintain blood pressure homeostasis, the effective circulating fluid volume and thereby body Na+ content has to be maintained within very narrow limits. From recent work in humans and rats, the notion has emerged that Na+ could be stored somewhere in the body without commensurate water retention to buffer free extracellular Na+, and that previously unidentified extrarenal, tissue-specific regulatory mechanisms are operative regulating the release and storage of Na+ from a kidney-independent reservoir. Moreover, immune cells from the mononuclear phagocyte system not only function as local on-site sensors of interstitial electrolyte concentration, but also, together with lymphatics, act as systemic regulators of body fluid volume and blood pressure. These studies have established new and unexpected targets in studies of blood pressure control and thus the pathophysiology of hypertension; the interstitium-/extracellular matrix of the skin, its inherent interstitial fluid and the lymphatic vasculature forming a vessel network in the interstitium. Aspects of the interstitium in relation to Na+ balance and hypertension are the focus of this review. Taken together, observations of salt storage in the skin to buffer free extracellular Na+ and macrophage modulation of the extracellular matrix and lymphatics suggest that electrolyte homeostasis in the body cannot be achieved by renal excretion alone, but also relies on extrarenal regulatory mechanisms.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-28T04:50:46.05557-05:0
      DOI: 10.1111/apha.13006
  • Cardioprotection gain with Apelin-13: a matter of signaling
    • Authors: Lionetti Vincenzo
      Abstract: Apelin-13, a biologically active C-terminal peptide resulting from maturation of preproapelin, is an effective post-conditioning mimetic agent which is mainly expressed in cardiomyocytes and coronary endothelial cells of failing heart.1-2 A significant effort to unravel the intricate signaling mechanisms of apelin 13-induced cardioprotection can be exemplified in an elegant study by Folino et al.3 in the current issue.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-27T11:17:15.243629-05:
      DOI: 10.1111/apha.13005
  • Thyroid hormone upregulates MDM2 in rat type i fiber: implications for
           skeletal muscle mass regulation
    • Authors: Gracielle Vieira Ramos; André Cruz, William Jose Silva, Andrei Rozanski, Igor Luchini Baptista, João Guilherme Silvestre, Anselmo Sigari Moriscot
      Abstract: AimBased upon a microarray assay, we have identified that triiodothyronine (T3) up-regulates MDM2 gene expression in the rat skeletal muscle. Since MDM2 protein is an E3 ligase, we hypothesized that this enzyme could play a role in T3 effects on skeletal muscle mass control.MethodsTo test our hypothesis, male rats (2 months old) were randomly assigned into the following groups: intact controls, treated with 20 physiological doses of T3 for 0.5, 1 and 7 days, or with 5, 20 and 50 physiological doses of T3 for 7 days. For in vitro experiments, myotubes were treated with T3 for 3 daysResultsAfter validation of the microarray finding throughout RT-PCR and confirmation that T3 induces increases in MDM2 protein expression in a dose dependent manner, we observed that MDM2 was up-regulated by T3 exclusively in fiber type I. Moreover, detailed histological evaluation showed that MDM2 overexpression distributes punctiformily along the cross section of the fiber and also inside nuclei. MDM2 co-localizes with PAX7 in control muscle and T3 down-regulates this myogenic factor. Pharmacological inhibition of MDM2 in cultured myotubes caused a severe decrease in their diameter (~35%, p
      PubDate: 2017-11-27T11:15:43.31193-05:0
      DOI: 10.1111/apha.13003
  • The Guardian of the Genome p53 Regulates Exercise-Induced Mitochondrial
           Plasticity Beyond Organelle Biogenesis
    • Authors: William J. Smiles; Donny M. Camera
      Abstract: The Guardian of the Genome p53 has been established as a potent tumor suppressor. However, culminating from seminal findings in rodents more than a decade ago, several studies have demonstrated that p53 is required to maintain basal mitochondrial function [i.e., respiration and reactive oxygen species (ROS) homeostasis]. Specifically, via its role(s) as a tumor suppressor, p53 intimately surveys cellular DNA damage, in particular mitochondrial DNA (mtDNA), to ensure that the mitochondrial network is carefully monitored and cell viability is upheld, since aberrant mtDNA damage leads to apoptosis and widespread cellular perturbations. Indeed, data from rodents and humans have demonstrated that p53 forms an integral component of the exercise-induced signal transduction network regulating skeletal muscle mitochondrial remodeling. In response to exercise-induced disruptions to cellular homeostasis that have the potential to harm mtDNA (e.g., contraction-stimulated ROS emissions), appropriate p53-regulated, mitochondrial turnover responses prevail to protect the genome and ultimately facilitate a shift from aerobic glycolysis to oxidative phosphorylation; adaptations critical for endurance-based exercise that are commensurate with p53's role as a tumor suppressor. Despite these observations, several discrepancies exist between rodent and human studies pinpointing p53 subcellular trafficking from nuclear to mitochondrial compartments following acute exercise. Such interspecies differences in p53 activity and the plausible p53-mediated adaptions to chronic exercise training will be discussed herein.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-27T11:15:35.34404-05:0
      DOI: 10.1111/apha.13004
  • Current Matters of the Heart
    • Authors: B. Persson; Anja Bondke Persson
      Abstract: Cardiac function and the development and adaption of the cardiovascular system are among the classics in physiology, and as such are also among the flagship topics in Acta Physiologica. We regularly revisit according topics as, e.g. arterial hypertension, renal function and channelopathies, to provide you with an overview of the latest novel developments in the field.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-25T10:40:25.247478-05:
      DOI: 10.1111/apha.13002
  • Effects of female sex hormones on folic acid-induced anti-angiogenesis
    • Authors: Wen-Sen Lee; Yi-Chen Lu, Chun-Ting Kuo, Chiung-Tong Chen, Pei-Hua Tang
      Abstract: AimPregnant women have been recommended to take FA daily to prevent birth defects in the brain and spinal cord. We previously showed that folic acid (FA) exerts an anti-angiogenic activity. Since angiogenesis is important for endometrial reorganization and embryonic development, there should be some mechanisms to allow the pregnant mother and the fetus to escape from the FA-induced anti-angiogenesis. The present study was designed to investigate the effect of female sex hormones on the FA-induced anti-angiogenic activity.MethodsThe protein levels and protein interaction were examined by Western blot analysis and immunoprecipitation assay, respectively. The cell proliferation and migration were examined by MTT and wound healing assays, respectively. The in vivo angiogenesis was evaluated by Matrigel angiogenesis assay.ResultsIn human umbilical venous endothelial cells (HUVEC), FA receptor (FR) formed a complex with progesterone receptor (PR), estradiol receptor (ER) and cSrc. Pregnancy levels of progesterone (P4) or estradiol (E2) prevented FA-induced inhibitions of proliferation and migration in HUVEC. Both E2 and P4 prevented the FA-induced anti-angiogenesis in vivo. Moreover, co-treatment with FA and P4 or E2 inhibited the signaling pathways involved in FA-induced inhibitions of proliferation and migration in HUVEC.ConclusionFemale sex hormones interrupt the FA-induced anti-angiogenic action through receptor-receptor interaction.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-25T10:40:23.802317-05:
      DOI: 10.1111/apha.13001
  • Gene expression and delayed nephrogenesis in the growth-restricted rat
           fetus and neonate
    • Authors: A.M. Carter
      Abstract: In this issue of Acta Physiologica, Cuffe et al. [1] explore the molecular mechanisms behind impaired nephrogenesis in a rat model of uteroplacental insufficiency and fetal growth restriction. Nephron development was delayed after growth restriction, continuing late into the postnatal period, and this was reflected in increased abundance of branching morphogenesis genes a week after birth.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-24T01:20:20.051936-05:
      DOI: 10.1111/apha.13000
  • Renal Hypoxia in Kidney Disease: Cause or Consequence'
    • Authors: Connie P. C. Ow; Jennifer P. Ngo, Md Mahbub Ullah, Lucinda M. Hilliard, Roger G. Evans
      Abstract: Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease and acute kidney injury, initiating and propagating a vicious cycle of tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (1) Is kidney disease always associated with tissue hypoxia' (2) Does tissue hypoxia drive signaling cascades that lead to tissue damage and dysfunction' (3) Does tissue hypoxia per se lead to kidney disease' (4) Does tissue hypoxia precede pathology' (5) Does tissue hypoxia co-localize with pathology' (6) Does prevention of tissue hypoxia prevent kidney disease' We conclude that tissue hypoxia is a common feature of both acute kidney injury and chronic kidney disease. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signaling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. co-localization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a ‘common pathway’ to both acute kidney injury and chronic kidney disease still remains to be adequately tested.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-21T02:25:37.928142-05:
      DOI: 10.1111/apha.12999
  • Deletion of the EGF-receptor in vascular smooth muscle cells prevents
           chronic angiotensin II-induced arterial wall stiffening and media
    • Authors: Barbara Schreier; Mirja Hünerberg, Sigrid Mildenberger, Sindy Rabe, Daniel Bethmann, Claudia Wickenhauser, Michael Gekle
      Abstract: AimIn vivo vascular smooth muscle cell (VSMC) EGF receptor (EGFR) contributes to acute angiotensin II (AII) effects on vascular tone and blood pressure. The ubiquitously expressed EGFR has been implicated in vascular remodeling preceding end-organ damage by pharmacological inhibition, and AII signaling in cultured vascular cells is partly EGFR dependent. However the role of VSMC-EGFR in vivo during AII-induced pathophysiological processes is not known.MethodsThe present study assesses the in vivo relevance of VSMC-EGFR during chronic AII challenge without further stressors, using a mouse model with inducible, VSMC-specific EGFR knock out (VSMC-EGFR-KO). In these mice functional and structural vascular, renal and cardiac effects or biomarkers were investigated in vivo and ex vivo.ResultsVSMC-EGFR-KO prevented AII-induced media hypertrophy of mesenteric arteries, renal arterioles and the aorta, VSMC ERK1/2-phosphorylation as well as the impairment of vascular compliance. Furthermore, induction of vascular fibrosis, creatinineamia, renal interstitial fibrosis as well as the increase in fractional water excretion were prevented. AII-induced increase of systolic blood pressure was mitigated. By contrast, endothelial dysfunction, induction of vascular inflammatory marker mRNA and albuminuria were not inhibited. Cardiac and cardiomyocyte hypertrophy were also not prevented by VSMC-EGFR-KO.ConclusionsVSMC-EGFRs are relevant for pathological AII action in vivo. Our data show in vivo and ex vivo the necessity of VSMC-EGFR for AII-induced structural and functional vascular remodeling, not including endothelial dysfunction. Hereby, VSMC-EGFR gains importance for complete AII-induced renal end-organ damage succeeding vascular remodeling.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-20T00:12:37.788043-05:
      DOI: 10.1111/apha.12996
  • Neuroplasticity following short-term strength training occurs at
           supraspinal level and is specific for the trained task
    • Authors: Louis-Solal Giboin; Benjamin Weiss, Felix Thomas, Markus Gruber
      Abstract: AimsDifferent modalities of strength training cause performance enhancements, which are specific for the trained task. However, the involved mechanisms are still largely unknown. It has been demonstrated that strength training could induce neuroplasticity, which might underlie the performance improvements during the first training sessions. Thus, we hypothesized to find task-specific neuroplasticity after a short-term strength training of two distinct strength tasks.MethodsYoung healthy male subjects were exposed to 4 sessions of either maximal isometric explosive (EXPL group, N = 9) or slow sustained (SUS group, N = 10) knee extensions. Pre- and post-training, we measured H-reflexes and motor evoked potentials (MEPs) in the vastus lateralis (VL) at the onset of both strength tasks.ResultsPre- and post-training, H-reflexes remained unchanged in both groups. MEP areas were lower in the trained task in both groups and remained unchanged in the untrained task.ConclusionThe present study demonstrated that short-term strength training induces specific neuroplasticity for the trained task only. The fact that MEPs were lower, but H-reflex amplitudes remained unchanged at the onset of the trained tasks suggests that strength training elicited neuroplasticity at supraspinal level that most likely reflect an improved task-specific corticospinal efficiency.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-16T11:10:23.455304-05:
      DOI: 10.1111/apha.12998
  • Understanding the functional role of microRNA-214-3p in atherosclerosis
           for the identification of novel targeted therapies to prevent or reverse
           endothelial cell dysfunction and stimulate autophagy
    • Authors: Adriana Georgescu
      Abstract: The original article by Jing Wang and collaborators, entitled “MicroRNA-214-3p: A Link between Autophagy and Endothelial Cell Dysfunction in Atherosclerosis”, brings new data concerning molecular mechanisms linking decreased autophagy to endothelial dysfunction in atherosclerosis. In this issue of Acta Physiologica, the authors concluded that microRNA-214-3p (miR-214-3p) controls oxidized low-density lipoprotein (ox-LDL)-induced autophagy in human umbilical vein endothelial cells (HUVECs) by regulating intracellular levels of autophagy-related protein 5 (ATG5), and may have a relevant role in the pathogenesis of atherosclerosis.This study was done through in vivo and in vitro experiments conducted in ApoE-/- mice supplied with high fat diet (HFD) as atherosclerosis model and HUVECs. In vivo experiments, ATG5, ATG12 and miR-214-3p levels were analysed in the purified CD31+ endothelial cells from mouse aorta. Interesting, prediction of the binding between miR-214-3p and 3′-UTR of ATG5 mRNA was performed by bioinformatics analyses. In vitro experiments, HUVECs were transfected in order to modulate miR-214-3p and stimulated with ox-LDL to induce a stress-repairing autophagic process.The authors showed in their experimental study three very important aspects: (1) in atherosclerotic mouse model, they identified an inverse correlation between miR-214-3p and ATG5 and ATG12; (2) in young HUVEC, they found ox-LDL induced autophagy as evidenced by the increases in ATG5, ATG12, and microtubule-associated protein 1 light chain 3 (LC3B) protein levels with a simultaneously decreased SQSTM1/p62 protein level, and miR-214-3p overexpression reduced autophagy; (3) in old HUVECs, inhibition of the miR-214-3p increased their protective autophagy response to the ox-LDL stimulus, as evaluated by autophagic protein analysis, LC3B immunofluorescence assay, and transmission electron microscopy (TEM) 1This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-16T02:20:19.686719-05:
      DOI: 10.1111/apha.12997
  • Renal haemodynamics and oxygenation during and after cardiac surgery and
           cardiopulmonary bypass
    • Authors: Roger G. Evans; Yugeesh R. Lankadeva, Andrew D. Cochrane, Bruno Marino, Naoya Iguchi, Michael Z.L. Zhu, Sally G. Hood, Julian A. Smith, Rinaldo Bellomo, Bruce S. Gardiner, Chang-Joon Lee, David W. Smith, Clive N. May
      Abstract: Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models, that medullary ischaemia and hypoxia occurs during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimisation of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of individual interventions. We propose a multidisciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review we outline the recent progress on each of these fronts.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-11T07:30:24.365966-05:
      DOI: 10.1111/apha.12995
  • Influence on jitter measurement of components from distant fibers in
           potential recorded by single fiber electrode
    • Authors: Ewa Zalewska; Malgorzata Gawel
      Abstract: Single-fiber electromyography (SFEMG) is one of the most important diagnostic tools for evaluating neuromuscular transmission and jitter as well as fiber density.1 When a motor axon is depolarized, the action potential travels distally and activates all the muscle fibers belonging to the same motor unit at more or less the same time. The variations in the time interval between firing of adjacent single muscle fibers from the same motor unit are called neuromuscular jitter and reflect abnormalities in the transmission time in axonal derivations and synapses.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-09T15:05:20.016342-05:
      DOI: 10.1111/apha.12994
  • Urethral afferent signalling: role of 5-HT paraneurons
    • Authors: K-E Andersson
      Abstract: In this issue of Acta Physiologica, Kullmann et al. examined the morphology and potential role in sensory signaling of a different class of specialized cells in mouse urethral epithelium that express serotonin (5-HT), termed paraneurons.1 They propose that the paraneurons function as important detectors and transmitters in the urethral sensory mechanisms.Signalling from the afferent nerves of the lower urinary tract (LUT) is required for sensation of pain, bladder filling, and initiation and maintenance of the micturition reflex.2 Afferent signaling can be generated by the contractile activity of the detrusor myocytes,3 but also by the mucosa.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-09T15:00:19.423631-05:
      DOI: 10.1111/apha.12993
  • Atrial natriuretic peptide reduces inflammation and enhances apoptosis in
           rat acute pancreatitis
    • Authors: Ana Clara Najenson; Ana Paula Courreges, Juan Carlos Perazzo, María Fernanda Rubio, Marcelo S. Vatta, Liliana G. Bianciotti
      Abstract: AimWe previously reported that atrial natriuretic peptide (ANP) reduces serum amylase and intrapancreatic trypsinogen activation in the onset of acute pancreatitis whereas secretin increases them. In the present work, we sought to establish the effect of ANP and secretin on the inflammatory response and cell death in experimental acute pancreatitis.MethodsThe expression and activity of key inflammatory mediators and apoptosis were evaluated in the presence or absence of the atrial peptide, secretin or both in cerulein-induced acute pancreatitis in rats. Also, ultrastructural changes in pancreatic acinar cells were assessed by transmission electron microscopy.ResultsANP significantly reduced NF-κB activation and TNF-α intrapancreatic levels. Furthermore, it decreased inducible nitric oxide synthase and cyclooxygenase 2 expression and activity while it diminished myeloperoxidase activity. ANP also stimulated apoptosis as shown by caspase 3 expression and activation as well as TUNEL assay. These findings correlated well with the ultrastructural changes observed in the exocrine pancreas. Although secretin reduced various inflammatory markers, it also diminished caspase-3 activation and the overall response was the aggravation of the disease as reflected by the ultrastructural alterations of pancreatic acinar cells. In the presence of ANP, various effects evoked by secretin were antagonized.ConclusionsPresent findings show that ANP significantly attenuated the severity of acute pancreatitis in the rat by inducing apoptosis and reducing the inflammatory response and further suggest that ANP may have eventual therapeutic implications in the disease and/or in medical interventions at risk of its developing like endoscopic retrograde cholangiopancreatography.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-08T15:00:25.041237-05:
      DOI: 10.1111/apha.12992
  • NSAIDs may blunt more than pain
    • Authors: Brad Schoenfeld
      Abstract: In this issue of Acta Physiologica, Lilja et al. 1 provide novel insights into the effects of consuming high-doses of non-steroidal anti-inflammatory drugs (NSAIDs) on exercise-induced muscular adaptations. NSAIDs are routinely administered to relieve symptoms associated with delayed onset muscle soreness (DOMS) and restore normal physical function following intense physical activity. Millions worldwide report the daily intake of NSAIDS, and their usage is especially common in athletes and those who partake in rigorous exercise 2.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-08T15:00:19.670861-05:
      DOI: 10.1111/apha.12990
  • One hundred thousand US Dollars to battle scientific logorrhea
    • Authors: P. B. Persson
      Abstract: This editorial may have remained unwritten, in the face of a lifetime word cap for scientists, which is regaining interest. (Give researchers a lifetime word limit, Brian C. Martinson, Nature).Providing us with a lifespan contingent of words for our scientific writing immediately solves many present-day glitches. No more minimal-publishing-units and redundant material will flood journals or aggravate reviewers.This article is protected by copyright. All rights reserved.
      PubDate: 2017-11-08T14:55:26.865254-05:
      DOI: 10.1111/apha.12991
  • Hypoxic sprint exercise as a complement to the “Live High Train
           Low” regime
    • Authors: Helene Rundqvist; Thomas Gustafsson
      Abstract: Despite decades of research and numerous studies, the evidence supporting altitude adaptation for lowlanders who intend to perform at or around sea level is still under debate. In a recent study, Girard and colleagues aimed to complement the general consensus that the “live high-train low” is the most advantageous regime by adding either normoxic (LHTL) or hypoxic (LHTLH) repeated sprint sessions to improve team-athlete performance.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-31T01:15:20.81053-05:0
      DOI: 10.1111/apha.12989
  • A practical guide to the preparation and use of metal ion-buffered systems
           for physiological research
    • Authors: Felix Neumaier; Serdar Alpdogan, Jürgen Hescheler, Toni Schneider
      Abstract: Recent recognition that mobile pools of Zn2+ and Cu2+ are involved in the regulation of neuronal, endocrine and other cells has stimulated the development of tools to visualize and quantify the level of free trace metal ions. Most of the methods used to measure or control loosely bound metals require reference media that contain exactly defined free concentrations of the target ions. Despite the central importance of proper metal ion buffering, there is still a lack of international standards and beginners in the field may have difficulties finding a coherent description of how to prepare trace metal ion buffers, especially when experiments are to be performed in multi-metal systems. To close this gap, we provide a guide for the design, preparation and use of metal ion buffered systems that facilitates immediate application under physiologically relevant ionic conditions. Relevant thermodynamic and kinetic concepts of chemical speciation as well as general protocols and specific examples are outlined for the accurate preparation of single- and dual-metal ion buffers. In addition, experiments have been performed with FluoZin-3 to illustrate that metal ion buffered systems are required for reliable preparation of nanomolar Zn2+ solutions and that dual-metal ion buffers can be used to calibrate suitable fluorescent Zn2+ sensors in the presence of physiological Ca2+ concentrations. Together, the information provided should sensitize readers to the many potential pitfalls and uncertainties that exist when working with physiologically-relevant concentrations of trace metal ions and enable them to formulate their own metal ion buffers for most in-vitro applications.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-24T02:55:25.80784-05:0
      DOI: 10.1111/apha.12988
  • Functional interaction of Junctophilin 2 with small conductance
    • Authors: Hong K. Fan; Tian X. Luo, Wei D. Zhao, Yong H. Mu, Yang Yang, Wen J. Guo, Hui Y. Tu, Qian Zhang
      Abstract: AimJunctophilins (JPs), a protein family of the junctional membrane complex, maintain the close conjunction between cell surface and intracellular membranes in striate muscle cells mediating the cross talk between extracellular Ca2+ entry and intracellular Ca2+ release. The small conductance Ca2+-activated K+ channels are activated by the intracellular calcium and play an essential role in the cardiac action potential profile. Molecular mechanisms of regulation of the SK channels are still uncertain. Here we sought to determine whether there is a functional interaction of junctophilin type 2(JP2) with the SK channels and whether JP2 gene silencing might modulate the SK channels function in cardiac myocytes.MethodsAssociation of JP2 with SK2 channel in mouse heart tissue as well as HEK 293 cells was studied using in vivo and in vitro approaches. siRNA knockdown of JP2 gene was assessed by Real time PCR. The expression of proteins was analyzed by Western blotting. Ca2+-activated K+ current (IK,Ca) in infected adult mouse cardiac myocytes was recorded using whole-cell voltage-clamp technique. The intracellular Ca2+ transient was measured using an IonOptix photometry system.ResultsWe showed for the first time that JP2 associates with the SK2 channel in native cardiac tissue. JP2, via the Membrane Occupation and Recognition Nexus (MORN motifs) in its N terminus, directly interacted with SK2 channels. A co-localization of the SK2 channel with its interaction protein of JP2 was found in the cardiac myocytes. Moreover, we demonstrated that JP2 is necessary for the proper cell-surface expression of the SK2 channel inHEK293. Functional experiments indicated that knockdown of JP2 caused a significant decrease in the density of IK,Ca and reduced the amplitude of the Ca2+ transient in infected cardiomyocytes.ConclusionsThe present data provide evidence that the functional interaction between JP2 and SK2 channels is present in the native mouse heart tissue. Junctophilin 2, as junctional membrane complex (JMC)protein, is an important regulator of the cardiac SK channels.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-21T03:45:23.256275-05:
      DOI: 10.1111/apha.12986
  • Acute mitogen activated protein kinase 1/2 inhibition improves functional
           recovery and vascular changes after ischemic stroke in rat- monitored by
           9.4 T Magnetic Resonance Imaging
    • Authors: Maryam Mostajeran; Friedrich Wetterling, Frank W Blixt, Lars Edvinsson, Saema Ansar
      Abstract: AimThe aim was to evaluate the beneficial effect of early mitogen activated protein kinase (MEK)1/2 inhibition administered at a clinical relevant time-point using the transient middle cerebral artery occlusion model and a dedicated rodent magnetic resonance imaging system (9.4T) to monitor cerebrovascular changes non-invasively for two weeks.MethodTransient middle cerebral artery occlusion was induced in male rats for two hours followed by reperfusion. The specific MEK1/2 inhibitor U0126 was administered i.p at 6 and 24 hours post-reperfusion. Neurological functions were evaluated by 6- and 28-point tests. 9.4 T magnetic resonance imaging was used to monitor morphological infarct changes at day 2, 8 and 14 after stroke and to evaluate cerebral perfusion at day 14.Immunohistochemistry evaluation of Ki67 was performed 14 days post-stroke.ResultsU0126 improved long-term behavioral outcome and significantly reduced infarct size. In addition, cerebral perfusion in U0126-treated animals was improved compared to the vehicle group. Immunohistochemistry showed a significant increase of Ki67+ cells in U0126 treated animals compared to the vehicle group.ConclusionEarly MEK1/2 inhibition improves long-term functional outcome, promotes recovery processes after stroke and most importantly provides a realistic time window for therapy.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-21T03:15:23.531766-05:
      DOI: 10.1111/apha.12985
  • Our best 2015-2017
    • Authors: P. B. Persson
      Abstract: Publishing, as everything else these days, is living in the fast lane. From writing to printing these words, our topmost original articles will have changed. Citations bode very well for Acta Physiologica, suggesting another stark increase in our impact factor after the large leap the impact factor took last year.1 Yet, what may interest authors and readers even more are the prospects for our Acta-Physiologica-Award, which is probably the greatest prize ever to be presented in recognition of scientific publishing.2 Being lean and muscular, Acta Physiologica rather publishes fewer, but better, manuscripts.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-21T02:35:26.700847-05:
      DOI: 10.1111/apha.12983
  • Uteroplacental insufficiency in rats induces renal apoptosis and delays
           nephrogenesis completion
    • Authors: James SM Cuffe; Jessica F. Briffa, Shannyn Rosser, Andrew L Siebel, Tania Romano, Deanne H. Hryciw, Mary E Wlodek, Karen M Moritz
      Abstract: AimUteroplacental insufficiency in rats reduces nephron endowment, leptin concentrations and programs cardiorenal disease in offspring. Cross-fostering growth restricted (Restricted) offspring onto a mother with normal lactation restores leptin concentrations and nephron endowment. This study aimed to determine if the reduced nephron endowment in Restricted offspring is due to delayed glomerular formation and dysregulation of renal genes regulating branching morphogenesis, apoptosis or leptin signalling. Furthermore, we aimed to investigate if cross-fostering Restricted offspring onto Control mothers could improve glomerular maturation and restore renal gene abundance.MethodsUteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on gestation day 18 (E18). Kidneys were collected at E20, postnatal day 1 (PN1) and PN7. An additional cohort was cross-fostered onto separate mothers at birth and kidneys collected at PN7.ResultsKidneys were lighter in the Restricted group, but weight was restored with cross-fostering. At E20, Bax, Flt1 and Vegfa abundance were increased in Restricted offspring, while Ret and Bcl2 transcripts were increased only in Restricted females. At PN7, Gdnf and Ret abundance were higher in Restricted offspring, as was Casp3. Restricted offspring had a wider nephrogenic zone with more immature glomeruli suggesting a delayed or extended nephrogenic period. Cross-fostering had subtle effects on gene abundance and glomerular maturity.ConclusionUteroplacental insufficiency induced apoptosis in the developing kidney and delayed and extended nephrogenesis. Cross-fostering Restricted offspring onto Control mothers had beneficial effects on kidney growth and renal maturity, which may contribute to the restoration of nephron endowment.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-19T03:10:26.116075-05:
      DOI: 10.1111/apha.12982
  • Knock-out of histamine receptor H3 alters adaptation to sudden darkness
           and monoamine levels in the zebrafish
    • Authors: Henri A. J. Puttonen; Maria Sundvik, Svetlana Semenova, Yukako Shirai, Yu-Chia Chen, Pertti Panula
      Abstract: AimHistamine receptor H3 has substantial neuropharmacological potential. Currently, knock-out models of this receptor have been investigated only in mice. We characterized the expression of this receptor in the zebrafish and generated a zebrafish histamine receptor H3 knock-out line. Using this model, we studied the role of histamine receptor H3 in important behaviours. We also analyzed the effect of histamine receptor H3 knock-out on monoaminergic systems, which has not been thoroughly studied in any animal model.MethodsGeneration of a mutant zebrafish line using the CRISPR/Cas9 system. Analysis of locomotor and social behaviour. Expression of histamine receptor H3 was characterized using in situ hybridization. Analysis of monoamine networks using HPLC, immunohistochemistry and quantitative PCR.ResultsWe found that histamine receptor H3 knock-out zebrafish larvae showed a shorter period of increased locomotion after a sudden onset of darkness, while the knock-out larvae had a wild type like acute response to sudden darkness. Adult knock-out fish showed decreased swimming velocity, although locomotor activity of knock-out larvae was unaltered. Additionally, levels of dopamine and serotonin were significantly decreased in the knock-out fish, while monoamine-related gene expression and immunohistochemistry patterns were unchanged.ConclusionsOur results show that histamine receptor H3 knock-out larvae adapt faster to sudden darkness, suggesting a role for this receptor in regulating responses to changes in the environment. The decreased levels of dopamine and serotonin provides the first direct evidence that knock-out of histamine receptor H3 alters these systems.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-16T17:41:00.407356-05:
      DOI: 10.1111/apha.12981
  • Muscle specific differences in expression and phosphorylation of the Janus
           kinase 2/ Signal Transducer and Activator of Transcription 3 following
           long-term mechanical ventilation and immobilization in rats
    • Authors: Heba Salah; Wen Fury, Jesper Gromada, Yu Bai, Tamar Tchkonia, James L. Kirkland, Lars Larsson
      Abstract: AimMuscle wasting is one of the factors most strongly predicting mortality and morbidity in critically ill intensive care unit (ICU). This muscle wasting affects both limb and respiratory muscles but the understanding of underlying mechanisms and muscle-specific differences remains incomplete. This study aims at investigating the temporal expression and phosphorylation of the Janus kinase / signal transducer and activator of transcription (JAK/STAT) pathway in muscle wasting associated with the ICU condition in order to characterize the JAK/STAT proteins and the related changes leading or responding to their activation during exposure to the ICU condition.MethodsA novel experimental ICU model allowing long-term exposure to the ICU condition, immobilization and mechanical ventilation, was used in this study. Rats were pharmacologically paralyzed by post-synaptic neuromuscular blockade and mechanically ventilated for durations varying between 6 hours and 14 days to study muscle-specific differences in the temporal activation of the JAK/STAT pathway in plantaris, intercostal and diaphragm muscles.ResultsThe JAK2/STAT3 pathway was significantly activated irrespective of muscle, but muscle-specific differences were observed in the temporal activation pattern between plantaris, intercostal, and diaphragm muscles.ConclusionThe JAK2/STAT3 pathway was differentially activated in plantaris, intercostal, and diaphragm muscles in response to the ICU condition. Thus, JAK2/STAT3 inhibitors may provide an attractive pharmacological intervention strategy in immobilized ICU patients, but further experimental studies are required in the study of muscle-specific effects on muscle mass and function in response to both short- and long-term exposure to the ICU condition prior to the translation into clinical research and practice.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-15T09:15:25.130559-05:
      DOI: 10.1111/apha.12980
  • Baroreflex sensitivity: an algebraic dilemma
    • Authors: Anna Taboni; Nazzareno Fagoni, Giovanni Vinetti, Guido Ferretti
      Abstract: The baroreflex system is a complex mechanism for short-term regulation of arterial blood pressure, involving the heart rate (HR), the heart contractility and the vascular tone in its efferent branches. The study of arterial baroreflexes relies on two different experimental approaches. On one hand, the closed-loop approach analyses the mutual relationship between HR and arterial blood pressure, both in steady state and in dynamic conditions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-11T02:15:19.631188-05:
      DOI: 10.1111/apha.12979
  • Molecular pathways of Estrogen receptors and β-adrenergic receptors in
           cardiac cells: Recognition of their similarities, interactions and
           therapeutic value
    • Authors: Machuki Ong'achwa Jeremiah; Hong-Yuan Zhang, Sian Harding, Hong Sun
      Abstract: Estrogen receptors (ERs) and β-adrenergic receptors (βARs) play important roles in the cardiovascular system. Moreover, these receptors are expressed in cardiac myocytes and vascular tissues. Numerous experimental observations support the hypothesis that similarities and interactions exist between the signaling pathways of ERs (ERα, ERβ, GPR30) and βARs (β1, β2, and β3AR). The recently discovered estrogen receptor GPR30 shares structural features with the βARs, and this forms the basis for the interactions and functional overlap. GPR30 possess protein kinase A (PKA) phosphorylation sites, PDZ binding motifs, and interacts with A-kinase anchoring protein 5 (AKAP5), all of which enable its interaction with the βARs pathways. The interactions between ERs and βARs occur downstream of the G protein-coupled receptor, through the Gαs and Gαi proteins. This review presents an up-to-date description of ERs and βARs and demonstrates functional synergism and interactions between these receptors in cardiac cells. We explore their signaling cascades and the mechanisms that orchestrate their interactions and propose new perspectives on the signaling patterns for the GPR30 based on its structural resemblance to the βARs. In addition, we explore the relevance of these interactions to cell physiology, drugs (especially β-blockers and calcium channels blockers), and cardioprotection. Furthermore, a receptor-independent mechanism for estrogen and its influence on the expression of βARs and calcium-handling proteins are discussed. Finally, we highlight promising therapeutic avenues that can be derived from the shared pathways, especially the phosphatidylinositol-3-OH kinase (PI3K/Akt) pathway.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-09T20:10:35.444901-05:
      DOI: 10.1111/apha.12978
  • Effects of manipulating tetanic calcium on the curvature of the
           force-velocity relationship in isolated rat soleus muscles
    • Authors: A. M. Kristensen; O. B. Nielsen, K Overgaard
      Abstract: AimIn dynamically contracting muscles, increased curvature of the force-velocity relationship contributes to the loss of power during fatigue. It has been proposed that fatigue-induced reduction in [Ca++]i causes this increased curvature. However, earlier studies on single fibers have been conducted at low temperatures. Here, we investigated the hypothesis that curvature is increased by reductions in tetanic [Ca++]i in isolated skeletal muscle at near-physiological temperatures.MethodsRat soleus muscles were stimulated at 60 Hz in standard Krebs–Ringer buffer and contraction force and velocity were measured. Tetanic [Ca++]i was in some experiments either lowered by addition of 10 μmol L−1 dantrolene or use of submaximal stimulation (30 Hz) or increased by addition of 2 mmol L−1 caffeine.Force-velocity curves were constructed by fitting shortening velocity at different loading forces to the Hill equation. Curvature was determined as the ratio a/F0 with increased curvature reflecting decreased a/F0.ResultsCompared to control levels, lowering tetanic [Ca++]i with dantrolene or reduced stimulation frequency decreased the curvature slightly as judged from increase in a/F0 of 13 ± 1% (P = < 0.001) and 20 ± 2% (P = < 0.001) respectively. In contrast, increasing tetanic [Ca++]i with caffeine increased the curvature (a/F0 decreased by 17 ± 1%; P = < 0.001).ConclusionContrary to our hypothesis, interventions that reduced tetanic [Ca++]i caused a decrease in curvature, while increasing tetanic [Ca++]i increased the curvature. These results reject a simple causal relation between [Ca++]i and curvature of the force-velocity relation during fatigue.This article is protected by copyright. All rights reserved.
      PubDate: 2017-10-03T10:40:23.372542-05:
      DOI: 10.1111/apha.12977
  • Mitochondrial increase in volume density with exercise training: more,
           larger or better'
    • Authors: Niels Ørtenblad
      Abstract: In this issue of Acta Physiologica, a paper by Meinild and colleagues1 aims to verify if the increase in mitochondrial content with endurance training is explained by mitochondrial remodelling (hypertrophy) or by a distinct biogenesis of new organelle structures. Mitochondria are membrane-enclosed organelles found in most cells, with a double membrane separating the mitochondrial matrix from the cytosol. This allows a permeability barrier enabling the electrochemical gradient, which in turn powers the cell aerobic ATP synthesis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-30T09:20:21.108244-05:
      DOI: 10.1111/apha.12976
  • Chemokine (C-X-C motif) ligand 1 is a myokine induced by palmitate and is
           required for myogenesis in mouse satellite cells
    • Authors: Shinya Masuda; Masashi Tanaka, Takayuki Inoue, Ryuji Kitano, Hajime Yamakage, Kazuya Muranaka, Toru Kusakabe, Akira Shimatsu, Koji Hasegawa, Noriko Satoh-Asahara
      Abstract: AimThe functional significance of the myokines, cytokines and peptides produced and released by muscle cells, has not been fully elucidated. The purpose of the present study was to identify a myokine with increased secretion levels in muscle cells due to saturated fatty acids and to examine the role of the identified myokine in the regulation of myogenesis.MethodsHuman primary myotubes and mouse C2C12 myotubes were used to identify the myokine; its secretion was stimulated by palmitate loading. The role of the identified myokine in the regulation of the activation, proliferation, differentiation and self-renewal was examined in mouse satellite cells (skeletal muscle stem cells).ResultsPalmitate loading promoted the secretion of chemokine (C-X-C motif) ligand 1 (CXCL1) in human primary myotubes, and it also increased CXCL1 gene expression level in C2C12 myotubes in a dose- and time-dependent manner. Palmitate loading increased the production of reactive oxygen species along with the activation of nuclear factor-kappa B (NF-κB) signalling. Pharmacological inhibition of NF-κB signalling attenuated the increase in CXCL1 gene expression induced by palmitate and hydrogen peroxide. Palmitate loading significantly increased CXC receptor 2 gene expression in undifferentiated cells. CXCL1 knockdown attenuated proliferation and myotube formation by satellite cells, with reduced self-renewal. CXCL1 knockdown also significantly decreased the Notch intracellular domain protein level.ConclusionThese results suggest that secretion of the myokine CXCL1 is stimulated by saturated fatty acids and that CXCL1 promotes myogenesis from satellite cells to maintain skeletal muscle homeostasis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-28T10:45:27.372643-05:
      DOI: 10.1111/apha.12975
  • SUMO co-expression modifies KV11.1 channel activity
    • Authors: Annette Buur Steffensen; Martin Nybo Andersen, Nancy Mutsaers, Amer Mujezinovic, Nicole Schmitt
      Abstract: AimThe voltage-gated potassium channel KV11.1 is the molecular basis for the IKr current which plays an important role in cardiac physiology. Its malfunction is associated with both inherited and acquired cardiac arrhythmias. Native currents differ from those in experimental models, suggesting additional regulatory mechanisms. We hypothesised that the post-translational modification sumoylation finetunes channel activity.MethodsThe functional effects of sumoylation on KV11.1 were addressed by employing two-electrode voltage-clamp (TEVC) experiments in Xenopus laevis oocytes. Site-directed mutagenesis enabled a further analyse of the SUMO-target amino acids. We assessed protein expression levels and used confocal imaging for localization studies.ResultsCo-expression with Ubc9 and SUMO alters the electrophysiological properties of KV11.1 leading to a decrease in steady-state current amplitude largely due to faster inactivation and alteration of deactivation kinetics. We identified three lysines (K21, K93, and K116) in the PAS-domain as the putative SUMO-targets.ConclusionThis study indicates KV11.1 as a sumoylation target, and offers the three main targets; K21, K93, and K116. Furthermore, it proposes an underlying mechanism for the observed kinetic impact of the PAS domain.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T10:40:24.684403-05:
      DOI: 10.1111/apha.12974
  • MicroRNA-214-3p: A Link between Autophagy and Endothelial Cell Dysfunction
           in Atherosclerosis
    • Authors: Jing Wang; Wei-Na Wang, Shuang-Bin Xu, Hong Wu, Bing Dai, Dong-Dong Jian, Mei Yang, Yu-Tao Wu, Qiang Feng, Jian-Hua Zhu, Lei Zhang, Li Zhang
      Abstract: AimEndothelial cell injury assumes a fundamental part in the pathogenesis of atherosclerosis, and endothelial cell autophagy has protective effects on the development of atherosclerosis, though the underlying molecular regulation mechanism is indistinct. This study is aimed to investigate whether microRNA-214-3p (miR-214-3p) is involved in the endothelial cell autophagy regulation of atherosclerosis.MethodsWe utilized ApoE-/- mice provided with a high-fat diet (HFD) as atherosclerosis model. We analyzed the level of miR-214-3p and the levels of autophagy-related protein 5 (ATG5) and autophagy-related protein 12 (ATG12) in the purified CD31+ endothelial cells from mouse aorta. Bioinformatics analysis and a dual luciferase reporter assay were performed to confirm the binding target of miR-214-3p. In vitro study, human umbilical vein endothelial cells (HUVECs) were transfected with miR-214-3p mimics/inhibitor and stimulated with 100 μg/mL oxidized low-density lipoprotein (ox-LDL) for 12 hours to initiate a stress-repairing autophagic process.ResultsIn mouse models, we identified an inverse correlation between miR-214-3p, ATG5 and ATG12. We observed that in young HUVECs, ox-LDL initiated autophagy where repressed by miR-214-3p overexpression, as evaluated by autophagic protein analysis, microtubule-associated protein 1 light chain 3B-II (LC3B-II) immunofluorescence assay, and transmission electron microscopy (TEM). Also, miR-214-3p promoted ox-LDL accumulation in HUVECs and THP-1 monocyte adhesion. Conversely, in old HUVECs, suppression of miR-214-3p preserved the ability to initiate a protective autophagy reaction to the ox-LDL stimulation.ConclusionmiR-214-3p regulates ox-LDL-initiated autophagy in HUVECs by directly targeting the 3'UTR of ATG5, and may have a suitable role in the pathogenesis of atherosclerosis.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T10:10:21.526414-05:
      DOI: 10.1111/apha.12973
  • Sphingosine-1-phosphate and renal vasoconstriction
    • Authors: Boye L Jensen
      Abstract: In the present issue of Acta Physiologica, Guan et al. in their article “Mechanisms of sphingosine-1-phosphate-mediated vasoconstriction of rat afferent arterioles” 1 address the signaling events associated with sphingosine-1-phosphate (S1P)-mediated renal afferent vasoconstriction and show in, technically demanding, blood-perfused juxtamedullary nephron preparation that S1P signaling relies predominantly on transmembrane calcium influx from the extracellular fluid through L-type calcium channels with contribution from oxidative stress metabolites1. So not only is new information on S1P signaling of potential therapeutic relevance obtained but the general concept is confirmed that renal preglomerular vascular reactivity relies significantly on calcium influx through voltage gated calcium channels.
      Authors showed previously, that S1P caused selective renal afferent but not efferent vasoconstriction2 and in conjunction with increased S1P release in pathophysiological situations like sepsis and ischemia-reperfusion incidents, this effect could be relevant in acute kidney injury with parallel decreases in renal blood flow and GFR.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T05:05:21.443658-05:
      DOI: 10.1111/apha.12971
  • Evaluating the essential role of RONS in vivo in exercised human muscle
    • Authors: Enrique Jaimovich; Mariana Casas
      Abstract: An article by Margaritelis et al.,1 (this issue) addresses an important issue in exercise physiology, as it is the actual role of reactive oxygen and nitrogen species (RONS) in exercise-induced adaptations in humans. The authors designed a procedure that allowed them to avoid the use of exogenous anti-oxidants and redox agents that will normally alter metabolism and have multiple undesired effects. We discuss here in the context of the necessary balance between the beneficial role of reactive oxygen and nitrogen species as intracellular signals for muscle adaptation and the deleterious effects of these species in oxidative stress.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-09T05:00:24.033232-05:
      DOI: 10.1111/apha.12972
  • ARMAX: A method for assessment of the dynamic response of the arterial
    • Authors: Morten T Lund; Max Salomonsson, Thomas E N Jonassen, Niels-Henrik Holstein-Rathlou
      Abstract: AimThe baroreflex is a key mechanism in cardiovascular regulation and alterations in baroreceptor function are seen in many diseases, including heart failure, obesity and hypertension. We propose a new method for analyzing baroreceptor function from continuous blood pressure and heart rate in both health and disease.Methods48-hour data series of blood pressure and heart rate were collected with telemetry. Sprague-Dawley rats on standard chow (n=11) served as controls, while rats on a high-fat, high-fructose diet (n=6) constituted the obese-hypertensive model. A third group of rats underwent autonomic blockade (n=6). An autoregressive–moving-average with exogenous inputs (ARMAX)-model was applied to the data and compared with the α-coefficient.ResultsAutonomic blockade caused a significant reduction in the strength of the baroreflex as estimated by ARMAX (ARMAX-BRS -0.03±0.01 vs. -0.19±0.04 bpm heartbeat-1). Both methods showed a ~50% reduction in BRS in the obese-hypertensive group compared with control (body weight 531±27 vs. 458±19 g, p
      PubDate: 2017-09-05T02:50:55.959159-05:
      DOI: 10.1111/apha.12962
  • Orexin A increases sympathetic nerve activity through promoting expression
           of proinflammatory cytokines in Sprague-Dawley rats
    • Authors: Yuanyuan Fan; Enshe Jiang, Taija Hahka, Qinghui Chen, Jianqun Yan, Zhiying Shan
      Abstract: AimAccumulating evidence suggests that orexin signaling is involved in the regulation of blood pressure and cardiovascular function. However, the underlying mechanisms are not clear. Here we test the hypothesis that upregulated orexin A signaling in the paraventricular nucleus (PVN) increases sympathetic nerve activity (SNA) through stimulating expression of proinflammatory cytokines (PICs).MethodsIn vivo sympathetic nerve recordings were performed to test the impact of PVN orexin signaling on sympathetic outflow in Sprague-Dawley (SD) rats. Real-time PCR was carried out to assess effects of central administration of orexin A on PVN PICs expression in SD rats. To test whether orexin A induced increases in PICs were exclusively mediated by orexin receptor 1 (OX1R), OX1R expressing PC12 (PC12-OX1R) cells were incubated with different dose of orexin A, then PICs mRNA and immunoreactivity were measured.ResultsOrexin A microinjection (25 pmol) into the PVN significantly increased splanchnic SNA (93.5%) and renal SNA (83.3%) in SD rats, and these increases were attenuated by OX1R antagonist SB408124. Intracerebroventricular injection of orexin A (0.2 nmol) into SD rats increased mRNA levels of PICs including IL1-β (2.7-fold), IL6 (1.7-fold) and TNF-α (1.5-fold), as well as Fra1 (1.6-fold) in the PVN. Orexin A treatment in PC12-OX1R cells resulted in a dose- and time-dependent increase in the expression of PICs and Fra1, a subunit of AP1 transcriptional factor. The increase in the PICs was blocked by AP1 blocker curcumin.ConclusionPVN orexin system activation is involved in SNA regulation maybe through triggering AP1-PICs pathway.This article is protected by copyright. All rights reserved.
      PubDate: 2017-09-05T02:45:28.061316-05:
      DOI: 10.1111/apha.12963
  • TRPM5 in the battle against diabetes and obesity
    • Authors: Rudi Vennekens; Margot Mesuere, Koenraad Philippaert
      Abstract: TRPM5 is a nonselective monovalent cation channel activated by increases of intracellular Ca2+. It has a distinct expression pattern: expression is detected in chemosensitive tissues from solitary chemosensory cells to the taste receptor cells and in pancreatic β-cells. The role of TRPM5 has been investigated with the use of knockout mouse models. Trpm5-/- mice have a lack of type II taste perception and show reduced glucose-induced insulin secretion. Expression levels of TRPM5 are reduced in obese, leptin signaling deficient mice and mutations in TRPM5 have been associated with type II diabetes and metabolic syndrome. In this review we aim to give an overview of the activation, selectivity, modulation and physiological roles of TRPM5.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-21T03:35:22.752212-05:
      DOI: 10.1111/apha.12949
  • High-doses of anti-inflammatory drugs compromise muscle strength and
           hypertrophic adaptations to resistance training in young adults
    • Authors: Mats Lilja; Mirko Mandić, William Apró, Michael Melin, Karl Olsson, Staffan Rosenborg, Thomas Gustafsson, Tommy R Lundberg
      Abstract: AimsThis study tested the hypothesis that high doses of anti-inflammatory drugs would attenuate the adaptive response to resistance training compared with low doses.MethodsHealthy men and women (aged 18-35 years) were randomly assigned to daily consumption of ibuprofen (IBU; 1200 mg; n=15) or acetylsalicylic acid (ASA; 75 mg; n=16) for 8 weeks. During this period, subjects completed supervised knee-extensor resistance training where one leg was subjected to training with maximal volitional effort in each repetition using a flywheel ergometer (FW), while the other leg performed conventional (work-matched across groups) weight-stack training (WS). Before and after training, muscle volume (MRI) and strength were assessed, and muscle biopsies were analysed for gene and protein expression of muscle growth regulators.ResultsThe increase in m. quadriceps volume was similar between FW and WS, yet was (averaged across legs) greater in ASA (7.5%) compared with IBU (3.7%, group difference 34 cm3; P=0.029). In the WS leg, muscle strength improved similarly (11-20%) across groups. In the FW leg, increases (10-23%) in muscle strength were evident in both groups yet they were generally greater (interaction effects P
      PubDate: 2017-08-21T02:40:24.716468-05:
      DOI: 10.1111/apha.12948
  • Contribution of Mitochondria-Derived Free Radicals to Endothelial
           Dysfunction in Human Skeletal Muscle Feed Arteries: Another Hazard of the
           Aging Process
    • Authors: Julian H. Lombard
      Abstract: Earlier studies by a number of laboratories 1-3 have demonstrated impaired endothelium-dependent vasodilation in arterioles of aged animals and humans; and older humans exhibit significantly attenuated hyperemic responses to moderate exercise1 and endothelium-dependent vasodilator stimuli 3 compared to younger controls, emphasizing the need for carefully targeted research to understand the mechanisms underlying compromised blood flow with age and its consequences. The current paper by Park and coworkers4 is a follow-up to an earlier study by this group,3 in which they demonstrated a significant attenuation of endothelium-dependent dilation in older subjects, compared to young subjects, which was accompanied by reductions in phospho-eNOS/eNOS (p-eNOS/eNOS) ratio and elevations in vascular superoxide (O2-) levels. The current study extends the authors’ earlier findings by investigating an important question, namely, whether mitochondria-derived free radicals are the mechanism responsible for the impaired endothelium-dependent vasodilator responses in the older individuals.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-21T02:35:19.491793-05:
      DOI: 10.1111/apha.12947
  • Autophagic dysfunction and autophagosome escape in the mdx mus musculus
           model of Duchenne muscular dystrophy
    • Authors: Hannah R. Spaulding; Ellen M. Kelly, John C. Quindry, Joel B. Sheffield, Matthew B. Hudson, Joshua T. Selsby
      Abstract: AimDuchenne muscular dystrophy is caused by the absence of functional dystrophin protein and results in a host of secondary effects. Emerging evidence suggests that dystrophic pathology includes decreased pro-autophagic signaling and suppressed autophagic flux in skeletal muscle, but the relationship between autophagy and disease progression is unknown. The purpose of this investigation was to determine the extent to which basal autophagy changes with disease progression. We hypothesized that autophagy impairment would increase with advanced disease.MethodsTo test this hypothesis, seven week old and 17 month old dystrophic diaphragms were compared to each other and age-matched controls.ResultsChanges in protein markers of autophagy indicate impaired autophagic stimulation through AMPK, however, robust pathway activation in dystrophic muscle, independent of disease severity. Relative protein abundance of p62, an inverse correlate of autophagic degradation, was dramatically elevated with disease regardless of age. Likewise, relative protein abundance of Lamp2, a lysosome marker, was decreased 2-fold at 17 months of age in dystrophic muscle and was confirmed, along with mislocalization, in histological samples, implicating lysosomal dysregulation in this process. In dystrophic muscle autophagosome-sized p62 positive foci were observed in the extracellular space. Moreover, we found that autophagosomes were released from both healthy and dystrophic diaphragms into the extracellular environment, and the occurrence of autophagosome escape was more frequent in dystrophic muscle.ConclusionThese findings suggest autophagic dysfunction proceeds independent of disease progression, blunted degradation of autophagosomes is due in part to decreased lysosome abundance, and contributes to autophagosomal escape to the extracellular space.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-19T05:05:23.182214-05:
      DOI: 10.1111/apha.12944
  • Comments on the Review “Biomarkers in acute kidney injury –
           pathophysiological basis and clinical performance” Acta Physiol 2017,
           219, 556–574: An update on kidney localization of IGFBP7 and TIMP2
    • Authors: David R. Emlet; Xiaoyan Wen, John A. Kellum
      Abstract: In March of 2017, Acta Physiologica published a special series on renoprotection, and one of the publications in that series was a review entitled “Biomarkers in acute kidney injury – pathophysiological basis and clinical performance”. This review described very well the current understanding of the pathophysiology, cellular localization, and clinical performance of the most important currently proposed biomarkers of AKI, to include insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases 2 (TIMP2). At the time that this review was accepted, no work had yet clearly identified the cellular localization of IGFBP7 and TIMP2 in the kidney, and that fact was correctly commented on in the review.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-09T07:55:19.786859-05:
      DOI: 10.1111/apha.12934
  • Can principles of the surface potential be combined with knowledge of
           natural products to reduce atrial rhythm disturbances'
    • Authors: H. Ni; K. Narsingani, H. Zhang, W. R. Giles
      PubDate: 2017-08-08T04:51:05.087351-05:
      DOI: 10.1111/apha.12918
  • Study of termination of postprandial gastric contractions in humans, dogs,
           and Suncus murinus: role of motilin- and ghrelin- induced strong
    • Authors: Takashi Mikami; Kazuma Ito, Hetzel Tartera Diaz, Per M. Hellström, Erito Mochiki, Shota Takemi, Toru Tanaka, Sachiko Tsuda, Takamichi Jogahara, Ichiro Sakata, Takafumi Sakai
      Abstract: AimStomach contractions show two types of specific patterns in many species, i.e., migrating motor contraction (MMC) and postprandial contractions (PPCs), in the fasting and fed state, respectively. We found gastric PPCs terminated with migrating strong contractions in humans, dogs, and suncus. In this study, we reveal the detailed characteristics and physiological implications of these strong contractions of PPC.MethodsHuman, suncus, and canine gastric contractions were recorded with a motility-monitoring ingestible capsule and a strain-gauge force transducer. The response of motilin and ghrelin and its receptor antagonist on the contractions were studied by using free-moving suncus.ResultsStrong gastric contractions were observed at the end of a PPC in human, dog, and suncus models, and we tentatively designated this contraction to be a postprandial giant contraction (PPGC). In the suncus, the PPGC showed the same property as those of a phase III contraction of MMC (PIII-MMC) in the duration, motility index, and response to motilin- or ghrelin-antagonist administration. Ghrelin antagonist administration in the latter half of the PPC (LH-PPC) attenuated gastric contraction prolonged the duration of occurrence of PPGC, as found in PII-MMC.ConclusionIt is thought that the first half of the PPC changed to PII-MMC and then terminated with PIII-MMC, suggesting that PPC consists of a digestive phase (the first half of the PPC) and a discharge phase (LH-PPC), and that LH-PPC is coincident with MMC. In this paper, we propose a new approach for the understanding of postprandial contractions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-08T04:05:19.880144-05:
      DOI: 10.1111/apha.12933
  • Overexpression of Integrin α11 Induces Cardiac Fibrosis in Mice
    • Authors: Andreas Romaine; Ida W. Sørensen, Cédric Zeltz, Ning Lu, Pugazendhi Murugan Erusappan, Arne Olav Melleby, Lili Zhang, Bård Bendiksen, Emma Louise Robinson, Jan Magnus Aronsen, Kate M Herum, Håvard Danielsen, Ivar Sjaastad, Geir Christensen, Donald Gullberg
      Abstract: AimTo understand the role of the collagen-binding integrin α11 in vivo we have used a classical approach of creating a mouse strain overexpressing integrin α11. A transgenic mouse strain overexpressing α11 in muscle tissues was analysed in the current study with special reference to the heart tissue.MethodsWe generated and phenotyped integrin α11 transgenic (TG) mice by echocardiography, magnetic resonance imaging and histology. Wild-type (WT) mice were subjected to aortic banding (AB) and the expression of integrin α11 was measured in flow cytometry sorted cardiomyocytes and non-myocytes.ResultsTG mice developed left ventricular concentric hypertrophy by 6 months, with increased collagen deposition and reactivation of mRNA encoding foetal genes associated with cardiovascular pathological remodelling compared to WT mice. Masson's trichrome staining revealed interstitial fibrosis, confirmed additionally by magnetic resonance imaging, and was found to be most prominent in the cardiac septum of TG but not WT mice. TG hearts expressed increased levels of transforming growth factor-β2 and -β3 and upregulated smooth muscle actin. Macrophage infiltration coincided with increased NFκB signalling in TG but not WT hearts. Integrin α11 expression was increased in both cardiomyocytes and non-myocyte cells from WT AB hearts compared to sham operated animals.ConclusionWe report for the first time that overexpression of integrin α11 induces cardiac fibrosis and left ventricular hypertrophy. This is a result of changes in intracellular hypertrophic signalling and secretion of soluble factors that increase collagen production in the heart.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-03T09:50:24.308619-05:
      DOI: 10.1111/apha.12932
  • The importance of the functional network between endothelial
           microparticles and late endothelial progenitor cells for understanding the
           physiological aspects of this new vascular repair system
    • Authors: Rosita A. Condorelli; Aldo E. Calogero, Sandro La Vignera
      Abstract: The article by Alexandru and colleagues, entitled “Microparticles of healthy origins improves endothelial progenitor cell dysfunction via microRNA transfer in an atherosclerotic hamster model”, represent an important advance in the physiology of the late endothelial progenitor cells (EPCs), documenting the complementary role played by endothelial microparticles (MPs) that play an active role in this repair system.This article is protected by copyright. All rights reserved.
      PubDate: 2017-08-03T09:45:21.182972-05:
      DOI: 10.1111/apha.12931
  • Distribution of muscle fiber conduction velocity for representative
           samples of motor units in the full recruitment range of the tibialis
           anterior muscle
    • Authors: Alessandro Del Vecchio; Francesco Negro, Francesco Felici, Dario Farina
      Abstract: AimMotor units are recruited in an orderly manner according to the size of motor neurons. Moreover, because larger motor neurons innervate fibers with larger diameters than smaller motor neurons, motor units should be recruited orderly according to their conduction velocity (MUCV). Because of technical limitations, these relations have been previously tested either indirectly or in small motor unit samples that revealed weak associations between motor unit recruitment threshold (RT) and MUCV. Here we analyze the relation between MUCV and RT for large samples of motor units.MethodsTen healthy volunteers completed a series of isometric ankle dorsiflexions at forces up to 70% of the maximum. Multi-channel surface electromyographic signals recorded from the tibialis anterior muscle were decomposed into single motor unit action potentials, from which the corresponding motor unit RT, MUCV, and action potential amplitude were estimated. Established relations between muscle fiber diameter and CV were used to estimate the fiber size.ResultsWithin individual subjects, the distributions of MUCV and fiber diameters were unimodal and did not show distinct populations. MUCV was strongly correlated with RT (mean (SD) R2 = 0.7 (0.09), p
      PubDate: 2017-08-01T09:05:52.096688-05:
      DOI: 10.1111/apha.12930
  • Different Solutions to Restoring Oxygen Delivery at Altitude
    • Authors: William .K. Milsom
      Abstract: Populations resident to high altitude have adapted to the demands of performance in low oxygen environments in different ways. The article by Ivy et al.1 provides new data allowing the authors to speculate on what specifically may have led to these alternate solutions.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-28T02:32:27.31023-05:0
      DOI: 10.1111/apha.12926
  • Genetic ablation of carbonic anhydrase IX disrupts gastric barrier
           function via claudin-18 downregulation and acid backflux
    • Authors: Taolang Li; Xuemei Liu, Brigitte Riederer, Katerina Nikolovska, Anurag Kumar Singh, Kari A. Mäkelä, Anna Seidler, Yongjian Liu, Gerolf Gros, Helmut Bartels, Karl Heinz Herzig, Ursula Seidler
      Abstract: AimThe study aims to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX).MethodsWe assessed the ability of CAIX knockout and WT gastric surface epithelial cells to withstand luminal acid load by measuring the pHi of exteriorized gastric mucosa in vivousing two photon confocal laser scanning microscopy. Cytokines and claudin-18A2 expression was analyzed by RT-PCR.ResultsCAIX knockout gastric surface epithelial cells showed significantly faster pHi-decline after luminal acid load compared to WT. Increased gastric mucosal IL-1β and iNOSexpression,but decreased claudin-18A2 (which confer acid resistance) were observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin-18 expression was different between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL-11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent theclaudin-18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL-1β. The treatment reduced the parietal cell loss in CAIX KO mice in the subsequent months.ConclusionsWe propose that CAIX converts protons that are either backflux or extruded from the cells rapidly to CO2 and H2O, contributing to tight junction protection and gastric epithelial pHi regulation. Lack of CAIX results in persistent acid backflux via claudin-18 downregulation, causing loss of parietal cells, hypergastrinemia and foveolar hyperplasia.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T03:05:37.721075-05:
      DOI: 10.1111/apha.12923
  • Extravasal albumin concentration modulates contractile responses of renal
           afferent arterioles
    • Authors: Xiang Gao; Zhi Zhao Liu, Hayar Mohammed, Zhengbing Zhuge, Ming Liu, En Yin Lai, Leif Jansson, Mattias Carlström, Andreas Patzak, A. Erik G Persson
      Abstract: AimAfferent arterioles (AA) hold a key position in the regulation of renal blood flow and glomerular filtration rate. Being the effector site of tubuloglomerular feedback the afferent arteriole contributes to the renal handling of sodium and fluid. Dehydration goes along with increased renal interstitial protein concentration. Here, the hypothesis was tested that extravasal protein concentration directly modulates afferent arteriolar tone; a mechanism which may contribute to body fluid volume control.MethodThe effect of increased extravasal albumin concentration on the vascular reactivity was investigated in renal AA and interlobar arteries of mice, rat renal AA, and in pancreatic islet arterioles.ResultsAlbumin (2% and 4% in the bath solution) significantly potentiated the contractile response of renal afferent arterioles induced by angiotensin II and adenosine, as well as their combination, compared to the control situation (0.1% albumin). Albumin did not influence the contractility of larger renal vessels or pancreatic islet arterioles. Mimicking the increase of the osmolality induced by 4% albumin by applying mannitol to the bath solution also increased the response of renal arterioles to Ang II. However, the effect was smaller compared to that of albumin. The nitric oxide bioavailability, measured by DAF-FM fluorescence, was reduced in afferent arterioles exposed to 4% albumin.ConclusionThe protein-induced modulation of AA tone is mediated by the increased osmolality as well as by NO scavenging. The results suggest a possible contribution of these mechanisms to the control of extracellular fluid volume via adjustment of renal blood flow and glomerular filtration rate.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T03:05:32.89983-05:0
      DOI: 10.1111/apha.12925
  • Apelin-induced Cardioprotection Against Ischemia/Reperfusion Injury: Roles
           of Epidermal Growth Factor and Src
    • Authors: Anna Folino; Lisa Accomasso, Claudia Giachino, Pier Giorgio Montarolo, Gianni Losano, Pasquale Pagliaro, Raffaella Rastaldo
      Abstract: AimApelin, the ligand of the G-protein-coupled-receptor (GPCR) APJ, exerts a postconditioning-like protection against ischemia-reperfusion injury through activation of PI3K-Akt-NO signalling. The pathway connecting APJ to PI3K is still unknown. Since other GPCR ligands act through transactivation of epidermal growth factor receptor (EGFR) via a matrix-metalloproteinase (MMP) or Src kinase, we investigated whether EGFR transactivation is involved in the following three features of apelin-induced cardioprotection: limitation of infarct size, suppression of contracture, and improvement of post-ischemic contractile recovery.MethodIsolated rat hearts underwent 30-min of global ischaemia and 2-hours of reperfusion. Apelin (0.5 μM), was infused during the first 20-min of reperfusion. EGFR, MMP or Src were inhibited to study the pathway connecting APJ to PI3K. Key components of RISK pathway, namely PI3K, guanylyl-cyclase or mitochondrial K+-ATP channels were also inhibited. Apelin-induced EGFR and PTEN phosphorylation were assessed. Left ventricular pressure and infarct size were measured.ResultsApelin-induced reductions of infarct size and myocardial contracture were prevented by inhibition of EGFR, Src, MMP, or RISK pathway. The involvement of EGFR was confirmed by its phosphorylation. However, neither direct EGFR nor MMP inhibition affected apelin-induced improvement of early post-ischemic contractile recovery, which was suppressed by Src and RISK inhibitors only. Apelin also increased PTEN-phosphorylation, which was removed by Src inhibition.ConclusionWhile EGFR and MMP limit infarct size and contracture, Src or RISK pathway inhibition abolishes the three features of cardioprotection. Src does not only transactivate EGFR, but also inhibits PTEN by phosphorylation, thus playing a crucial role in apelin-induced cardioprotection.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-27T03:05:29.92916-05:0
      DOI: 10.1111/apha.12924
  • Cerebrocortical activity during self-paced exercise in temperate, hot and
           hypoxic conditions
    • Authors: J. D. Périard; K. De Pauw, F. Zanow, S. Racinais
      Abstract: AimHeat stress and hypoxia independently influence cerebrocortical activity and impair prolonged exercise performance. This study examined the relationship between electroencephalography (EEG) activity and self-paced exercise performance in control (CON, 18 °C, 40% RH), hot (HOT, 35 °C, 60% RH) and hypoxic (HYP, 18 °C, 40% RH FiO2: 0.145) conditions.MethodsEleven well-trained cyclists completed a 750 kJ cycling time trial in each condition on separate days in a counterbalanced order. EEG activity was recorded with α- and β-activity evaluated in the frontal (F3 and F4) and central (C3 and C4) areas. Standardized low-resolution brain electromagnetic tomography (sLORETA) was also utilized to localize changes in cerebrocortical activity.ResultsBoth α- and β-activity decreased in the frontal and central areas during exercise in HOT relative to CON (P < 0.05). α-activity was also lower in HYP compared with CON (P < 0.05), whereas β-activity remained similar. β-activity was higher in HYP than in HOT (P < 0.05). sLORETA revealed that α- and β-activity increased at the onset of exercise in the primary somatosensory and motor cortices in CON and HYP, while only β-activity increased in HOT. A decrease in α- and β-activity occurred thereafter in all conditions, with α-activity being lower in the somatosensory and somatosensory association cortices in HOT relative to CON.ConclusionHigh-intensity prolonged self-paced exercise induces cerebrocortical activity alterations in areas of the brain associated with the ability to inhibit conflicting attentional processing under hot and hypoxic conditions, along with the capacity to sustain mental readiness and arousal under heat stress.
      PubDate: 2017-07-25T05:16:21.06731-05:0
      DOI: 10.1111/apha.12916
  • MICAL2 Promotes Breast Cancer Cell Migration by Maintaining EGFR Stability
           and EGFR/P38 Signaling Activation
    • Authors: Yueyuan Wang; Wenjie Deng, Yujie Zhang, Shixiu Sun, Shuo Zhao, Yan Chen, Xuyang Zhao, Lei Liu, Jun Du
      Abstract: AimMICAL2, a cytoskeleton dynamics regulator, is identified associated with survival and metastasis of several types of cancers recently. The present study was designed to investigate the role of MICAL2 in breast cancer cell migration as well as its underlying mechanisms.MethodsThe relationship between MICAL2 and EGF/EGFR signaling was analyzed by using gene overexpression and knockdown techniques. Cell migration was measured by wound healing assays. Activation of EGF/EGFR singaling pathways were evaluated by immunofluorescence, qPCR, Western blotting and zymography techniques. Rac1 activity was assessed by pulldown assay. Correlation of MICAL2 and EGFR in breast cancer specimens was examined by using immunohistochemical analysis.ResultsEctopic expression of MICAL2 in MCF-7 cells augmented EGFR protein level, accompanied by the promotion of cell migration. Silencing MICAL2 in MDA-MB-231 cells destabilized EGFR and inhibited cell migration. In mechanism, the maintaining effect of MICAL2 on EGFR protein content was due to a delay in EGFR degradation. Expression of MICAL2 was also shown positively correlated with the activation of P38/HSP27 and P38/MMP9 signalings, which are the main downstream signaling cascades of EGF/EGFR involved in cell migration. Further analysis indicated that Rac1 activation contributed to the maintaining effect of MICAL2 on EGFR stability. In addition, analysis of breast cancer specimens revealed a positive correlation between MICAL2 and EGFR levels and an association between MICAL2 expression and worse prognosis.ConclusionMICAL2 is a major regulator of breast cancer cell migration, maintaining EGFR stability and subsequent EGFR/P38 signaling activation through inhibiting EGFR degradation in a Rac1-dependent manner.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:29:42.157585-05:
      DOI: 10.1111/apha.12920
  • Discovering Long-Term Potentiation (LTP) - Recollections and Reflections
           on what came after
    • Authors: Terje Lømo
      Abstract: Chance events led me to a lifelong career in scientific research. They paved the way for being the first to see long-term potentiation of synaptic efficiency (LTP) in Per Andersen's lab in Oslo in 1966. Here I describe my way to this discovery and the experiments with Tim Bliss in 1968-1969 that led to Bliss and Lømo, 1973. Surprisingly, we later failed to reproduce these results. I discuss possible reasons for this failure, which made us both leave LTP research, in my case for good, in Tim's case for several years.After 30 years of work in a different field, I renewed my interest in the hippocampus and LTP in the early 2000's and published, for the first time, results that I had obtained 40 years earlier. Here I present my take on how interest in and research on LTP evolved after the early years. This includes a discussion of the functions of hippocampus as seen in those early days, the case of patient H.M., Donald Hebb's place in the story, the search for “memory molecules” such as PKMζ, and the primary site for LTP expression (pre- and/or postsynaptic'). Throughout, I reflect on my life in science, how science is done, and what drives it. The reflections are quite personal and I admit to mixed feelings about broadcasting them.This article is protected by copyright. All rights reserved.
      PubDate: 2017-07-18T10:29:36.153794-05:
      DOI: 10.1111/apha.12921
  • Exercise training increases skeletal muscle mitochondrial volume density
           by enlargement of existing mitochondria and not de novo biogenesis
    • Authors: A.-K. Meinild Lundby; R. A. Jacobs, S. Gehrig, J. Leur, M. Hauser, T. C. Bonne, D. Flück, S. Dandanell, N. Kirk, A. Kaech, U. Ziegler, S. Larsen, C. Lundby
      Abstract: Aims(i) To determine whether exercise-induced increases in muscle mitochondrial volume density (MitoVD) are related to enlargement of existing mitochondria or de novo biogenesis and (ii) to establish whether measures of mitochondrial-specific enzymatic activities are valid biomarkers for exercise-induced increases in MitoVD.MethodSkeletal muscle samples were collected from 21 healthy males prior to and following 6 weeks of endurance training. Transmission electron microscopy was used for the estimation of mitochondrial densities and profiles. Biochemical assays, western blotting and high-resolution respirometry were applied to detect changes in specific mitochondrial functions.ResultMitoVD increased with 55 ± 9% (P < 0.001), whereas the number of mitochondrial profiles per area of skeletal muscle remained unchanged following training. Citrate synthase activity (CS) increased (44 ± 12%, P < 0.001); however, there were no functional changes in oxidative phosphorylation capacity (OXPHOS, CI+IIP) or cytochrome c oxidase (COX) activity. Correlations were found between MitoVD and CS (P = 0.01; r = 0.58), OXPHOS, CI+CIIP (P = 0.01; R = 0.58) and COX (P = 0.02; R = 0.52) before training; after training, a correlation was found between MitoVD and CS activity only (P = 0.04; R = 0.49). Intrinsic respiratory capacities decreased (P < 0.05) with training when respiration was normalized to MitoVD. This was not the case when normalized to CS activity although the percentage change was comparable.ConclusionsMitoVD was increased by inducing mitochondrial enlargement rather than de novo biogenesis. CS activity may be appropriate to track training-induced changes in MitoVD.
      PubDate: 2017-07-06T05:06:04.155931-05:
      DOI: 10.1111/apha.12905
  • Myoendothelial coupling through Cx40 contributes to EDH-induced
           vasodilation in murine renal arteries: evidence from experiments and
    • Authors: J. C. Brasen; C. de Wit, C. M. Sorensen
      Abstract: Regulation of renal vascular resistance plays a major role in controlling arterial blood pressure. The endothelium participates in this regulation as endothelial derived hyperpolarization plays a significant role in smaller renal arteries and arterioles, but the exact mechanisms are still unknown.AimTo investigate the role of vascular gap junctions and potassium channels in the renal endothelial derived hyperpolarization.MethodsIn interlobar arteries from wild-type and connexin40 knockout mice, we assessed the role of calcium-activated small (SK) and intermediate (IK) conductance potassium channels. The role of inward rectifier potassium channels (Kir) and Na+/K+-ATPases was evaluated as was the contribution from gap junctions. Mathematical models estimating diffusion of ions and electrical coupling in myoendothelial gap junctions were used to interpret the results.ResultsLack of connexin40 significantly reduces renal endothelial hyperpolarization. Inhibition of SK and IK channels significantly attenuated renal EDH to a similar degree in wild-type and knockout mice. Inhibition of Kir and Na+/K+-ATPases affected the response in wild-type and knockout mice but at different levels of stimulation. The model confirms that activation of endothelial SK and IK channels generates a hyperpolarizing current that enters the vascular smooth muscle cells. Also, extracellular potassium increases sufficiently to activate Kir and Na+/K+-ATPases.ConclusionRenal endothelial hyperpolarization is mainly initiated by activation of IK and SK channels. The model shows that hyperpolarization can spread through myoendothelial gap junctions but enough potassium is released to activate Kir and Na+/K+-ATPases. Reduced coupling seems to shift the signalling pathway towards release of potassium. However, an alternative pathway also exists and needs to be investigated.
      PubDate: 2017-07-02T23:41:17.88001-05:0
      DOI: 10.1111/apha.12906
  • Obesity gets on your renal nerves
    • Authors: B. L. Jensen
      PubDate: 2017-06-20T23:25:50.967591-05:
      DOI: 10.1111/apha.12900
  • Isopimaric acid – a multi-targeting ion channel modulator reducing
           excitability and arrhythmicity in a spontaneously beating mouse atrial
           cell line
    • Authors: S. Salari; M. Silverå Ejneby, J. Brask, F. Elinder
      Abstract: AimAtrial fibrillation is the most common persistent cardiac arrhythmia, and it is not well controlled by present drugs. Because some resin acids open voltage-gated potassium channels and reduce neuronal excitability, we explored the effects of the resin acid isopimaric acid (IPA) on action potentials and ion currents in cardiomyocytes.MethodsSpontaneously beating mouse atrial HL-1 cells were investigated with the whole-cell patch-clamp technique.Results1–25 μmol L−1 IPA reduced the action potential frequency by up to 50%. The effect of IPA on six different voltage-gated ion channels was investigated; most voltage-dependent parameters of ion channel gating were shifted in the negative direction along the voltage axis, consistent with a hypothesis that a lipophilic and negatively charged compound binds to the lipid membrane close to the positively charged voltage sensor of the ion channels. The major finding was that IPA inactivated sodium channels and L- and T-type calcium channels and activated the rapidly activating potassium channel and the transient outward potassium channel. Computer simulations of IPA effects on all of the ion currents were consistent with a reduced excitability, and they also showed that effects on the Na channel played the largest role to reduce the action potential frequency. Finally, induced arrhythmia in the HL-1 cells was reversed by IPA.ConclusionLow concentrations of IPA reduced the action potential frequency and restored regular firing by altering the voltage dependencies of several voltage-gated ion channels. These findings can form the basis for a new pharmacological strategy to treat atrial fibrillation.
      PubDate: 2017-06-09T07:25:28.007872-05:
      DOI: 10.1111/apha.12895
  • Age-related endothelial dysfunction in human skeletal muscle feed
           arteries: the role of free radicals derived from mitochondria in the
    • Authors: S.-Y. Park; O. S. Kwon, R. H. I. Andtbacka, J. R. Hyngstrom, V. Reese, M. P. Murphy, R. S. Richardson
      Abstract: AimThis study sought to determine the role of free radicals derived from mitochondria in the vasculature in the recognized age-related endothelial dysfunction of human skeletal muscle feed arteries (SMFAs).MethodsA total of 44 SMFAs were studied with and without acute exposure to the mitochondria-targeted antioxidant MitoQ and nitric oxide synthase (NOS) blockade. The relative abundance of proteins from the electron transport chain, phosphorylated (p-) to endothelial (e) NOS ratio, manganese superoxide dismutase (MnSOD) and the mitochondria-derived superoxide (O2−) levels were assessed in SMFA. Endothelium-dependent and endothelium-independent SMFA vasodilation was assessed in response to flow-induced shear stress, acetylcholine (ACh) and sodium nitroprusside (SNP).ResultsMitoQ restored endothelium-dependent vasodilation in the old to that of the young when stimulated by both flow (young: 68 ± 5; old: 25 ± 7; old + MitoQ 65 ± 9%) and ACh (young: 97 ± 4; old: 59 ± 10; old + MitoQ: 98 ± 5%), but did not alter the initially uncompromised, endothelium-independent vasodilation (SNP). Compared to the young, MitoQ in the old diminished the initially elevated mitochondria-derived O2− levels and appeared to attenuate the breakdown of MnSOD. Furthermore, MitoQ increased the ratio of p-eNOS to NOS and the restoration of endothelium-dependent vasodilation in the old by MitoQ was ablated by NOS blockade.ConclusionThis study demonstrated that MitoQ reverses age-related vascular dysfunction by what appears to be an NO-dependent mechanism in human SMFAs. These findings suggest that mitochondria-targeted antioxidants may have utility in terms of counteracting the attenuated blood flow and vascular dysfunction associated with advancing age.
      PubDate: 2017-06-08T01:00:47.733582-05:
      DOI: 10.1111/apha.12893
  • Neurological and neuropsychological effects of low and moderate prenatal
           alcohol exposure
    • Authors: E. Comasco; J. Rangmar, U. J. Eriksson, L. Oreland
      Abstract: Several explanations for the diverse results in research on foetal alcohol spectrum disorders or alcohol-related neurodevelopmental disorder might be at hand: timing, amount and patterns of alcohol exposure, as well as complex epigenetic responses. The genetic background of the offspring and its interaction with other prenatal and post-natal environmental cues are likely also of importance. In the present report, key findings about the possible effects of low and moderate doses of maternal alcohol intake on the neuropsychological development of the offspring are reviewed and plausible mechanisms discussed. Special focus is put on the serotonergic system within developmental and gene–environment frameworks. The review also suggests guidelines for future studies and also summarizes some of to-be-answered questions of relevance to clinical practice. Contradictory findings and paucity of studies on the effects of exposure to low alcohol levels during foetal life for the offspring's neuropsychological development call for large prospective studies, as well as for studies including neuroimaging and multi-omics analyses to dissect the neurobiological underpinnings of alcohol exposure-related phenotypes and to identify biomarkers. Finally, it remains to be investigated whether any safe threshold of alcohol drinking during pregnancy can be identified.
      PubDate: 2017-05-30T01:15:44.383986-05:
      DOI: 10.1111/apha.12892
  • Weak by the machines: muscle motor protein dysfunction – a side effect
           of intensive care unit treatment
    • Authors: O. Friedrich; S. Diermeier, L. Larsson
      Abstract: Intensive care interventions involve periods of mechanical ventilation, sedation and complete mechanical silencing of patients. Critical illness myopathy (CIM) is an ICU-acquired myopathy that is associated with limb muscle weakness, muscle atrophy, electrical silencing of muscle and motor proteinopathy. The hallmark of CIM is a preferential muscle myosin loss due to increased catabolic and reduced anabolic activity. The ubiquitin proteasome pathway plays an important role, apart from recently identified novel mechanisms affecting non-lysosomal protein degradation or autophagy. CIM is not reproduced by pure disuse atrophy, denervation atrophy, steroid-induced atrophy or septic myopathy, although combinations of high-dose steroids and denervation can mimic CIM. New animal models of critical illness and ICU treatment (i.e. mechanical ventilation and complete immobilization) provide novel insights regarding the time course of protein synthesis and degradation alterations, and the role of protective chaperone activities in the process of myosin loss. Altered mechano-signalling seems involved in triggering a major part of myosin loss in experimental CIM models, and passive loading of muscle potently ameliorates the CIM phenotype. We provide a systematic overview of similarities and distinct differences in the signalling pathways involved in triggering muscle atrophy in CIM and isolated trigger factors. As preferential myosin loss is mostly determined from biochemistry analyses providing no spatial resolution of myosin loss processes within myofibres, we also provide first results monitoring myosin signal intensities during experimental ICU intervention using multi-photon Second Harmonic Generation microscopy. Our results confirm that myosin loss is an evenly distributed process within myofibres rather than being confined to hot spots.
      PubDate: 2017-05-03T05:20:54.646332-05:
      DOI: 10.1111/apha.12885
  • The role of neuropeptide W in energy homeostasis
    • Authors: H. Li; S. J. Kentish, G. A. Wittert, A. J. Page
      Abstract: Neuropeptide W is the endogenous ligand for G-protein-coupled receptors GPR7 and GPR8. In this review, we summarize findings on the distribution of neuropeptide W and its receptors in the central nervous system and the periphery, and discuss the role of NPW in food intake and energy homeostasis.
      PubDate: 2017-05-03T05:15:30.064186-05:
      DOI: 10.1111/apha.12884
  • Transcriptional regulation of voltage-gated Ca2+ channels
    • Authors: R. González-Ramírez; R. Felix
      Abstract: The transcriptional regulation of voltage-gated Ca2+ (CaV) channels is an emerging research area that promises to improve our understanding of how many relevant physiological events are shaped in the central nervous system, the skeletal muscle and other tissues. Interestingly, a picture of how transcription of CaV channel subunit genes is controlled is evolving with the identification of the promoter regions required for tissue-specific expression and the identification of transcription factors that control their expression. These promoters share several characteristics that include multiple transcriptional start sites, lack of a TATA box and the presence of elements conferring tissue-selective expression. Likewise, changes in CaV channel expression occur throughout development, following ischaemia, seizures or chronic drug administration. This review focuses on insights achieved regarding the control of CaV channel gene expression. To further understand the complexities of expression and to increase the possibilities of detecting CaV channel alterations causing human disease, a deeper knowledge on the structure of the 5′ upstream regions of the genes encoding these remarkable proteins will be necessary.
      PubDate: 2017-04-20T23:10:16.710869-05:
      DOI: 10.1111/apha.12883
  • Exercise and epigenetic inheritance of disease risk
    • Authors: J. Denham
      Abstract: Epigenetics is the study of gene expression changes that occur in the absence of altered genotype. Current evidence indicates a role for environmentally induced alterations to epigenetic modifications leading to health and disease changes across multiple generations. This phenomenon is called intergenerational or transgenerational epigenetic inheritance of health or disease. Environmental insults, in the form of toxins, plastics and particular dietary interventions, perturb the epigenetic landscape and influence the health of F1 through to F4 generations in rodents. There is, however, the possibility that healthy lifestyles and environmental factors, such as exercise training, could lead to favourable, heritable epigenetic modifications that augment transcriptional programmes protective of disease, including metabolic dysfunction, heart disease and cancer. The health benefits conferred by regular physical exercise training are unquestionable, yet many of the molecular changes may have heritable health implications for future generations. Similar to other environmental factors, exercise modulates the epigenome of somatic cells and researchers are beginning to study exercise epigenetics in germ cells. The germ cell epigenetic modifications affected by exercise offer a molecular mechanism for the inheritance of health and disease risk. The aims of this review are to: (i) provide an update on the expanding field of exercise epigenetics; (ii) offer an overview of data on intergenerational/transgenerational epigenetic inheritance of disease by environmental insults; (iii) to discuss the potential of exercise-induced intergenerational inheritance of health and disease risk; and finally, outline potential mechanisms and avenues for future work on epigenetic inheritance through exercise.
      PubDate: 2017-04-19T01:11:11.36314-05:0
      DOI: 10.1111/apha.12881
  • Mind the gap: mechanisms regulating the endothelial barrier
    • Authors: M. Y. Radeva; J. Waschke
      Abstract: The endothelial barrier consists of intercellular contacts localized in the cleft between endothelial cells, which is covered by the glycocalyx in a sievelike manner. Both types of barrier-forming junctions, i.e. the adherens junction (AJ) serving mechanical anchorage and mechanotransduction and the tight junction (TJ) sealing the intercellular space to limit paracellular permeability, are tethered to the actin cytoskeleton. Under resting conditions, the endothelium thereby builds a selective layer controlling the exchange of fluid and solutes with the surrounding tissue. However, in the situation of an inflammatory response such as in anaphylaxis or sepsis intercellular contacts disintegrate in post-capillary venules leading to intercellular gap formation. The resulting oedema can cause shock and multi-organ failure. Therefore, maintenance as well as coordinated opening and closure of interendothelial junctions is tightly regulated. The two principle underlying mechanisms comprise spatiotemporal activity control of the small GTPases Rac1 and RhoA and the balance of the phosphorylation state of AJ proteins. In the resting state, junctional Rac1 and RhoA activity is enhanced by junctional components, actin-binding proteins, cAMP signalling and extracellular cues such as sphingosine-1-phosphate (S1P) and angiopoietin-1 (Ang-1). In addition, phosphorylation of AJ components is prevented by junction-associated phosphatases including vascular endothelial protein tyrosine phosphatase (VE-PTP). In contrast, inflammatory mediators inhibiting cAMP/Rac1 signalling cause strong activation of RhoA and induce AJ phosphorylation finally leading to endocytosis and cleavage of VE-cadherin. This results in dissolution of TJs the outcome of which is endothelial barrier breakdown.
      PubDate: 2017-03-22T03:50:49.020762-05:
      DOI: 10.1111/apha.12860
  • Repeated maximal-intensity hypoxic exercise superimposed to hypoxic
           residence boosts skeletal muscle transcriptional responses in elite
           team-sport athletes
    • Authors: F. Brocherie; G. P. Millet, G. D'Hulst, R. Van Thienen, L. Deldicque, O. Girard
      Abstract: AimTo determine whether repeated maximal-intensity hypoxic exercise induces larger beneficial adaptations on the hypoxia-inducible factor-1α pathway and its target genes than similar normoxic exercise, when combined with chronic hypoxic exposure.MethodsLowland elite male team-sport athletes underwent 14 days of passive normobaric hypoxic exposure [≥14 h·day−1 at inspired oxygen fraction (FiO2) 14.5–14.2%] with the addition of six maximal-intensity exercise sessions either in normobaric hypoxia (FiO2 ~14.2%; LHTLH; n = 9) or in normoxia (FiO2 20.9%; LHTL; n = 11). A group living in normoxia with no additional maximal-intensity exercise (LLTL; n = 10) served as control. Before (Pre), immediately after (Post-1) and 3 weeks after (Post-2) the intervention, muscle biopsies were obtained from the vastus lateralis.ResultsHypoxia-inducible factor-1α subunit, vascular endothelial growth factor, myoglobin, peroxisome proliferator-activated receptor-gamma coactivator 1-α and mitochondrial transcription factor A mRNA levels increased at Post-1 (all P ≤ 0.05) in LHTLH, but not in LHTL or LLTL, and returned near baseline levels at Post-2. The protein expression of citrate synthase increased in LHTLH (P 
      PubDate: 2017-02-22T00:15:33.898929-05:
      DOI: 10.1111/apha.12851
  • Sprint exercise enhances skeletal muscle p70S6k phosphorylation and more
           so in females than in males
    • Authors: Mona Esbjörnsson; Håkan C Rundqvist, Henrik Mascher, Ted Österlund, O. Rooyackers, Eva Blomstrand, Eva Jansson
      Abstract: Aim:Sprint exercise is characterized by repeated sessions of brief intermittent exercise at a high relative workload. However, little is known about the effect on mTOR pathway, an important link in regulation of muscle protein synthesis. An earlier training study showed a greater increase in muscle fibre cross sectional area in females than males. Therefore, we tested the hypothesis that activation of mTOR signalling is more pronounced in females than in males. Healthy males (n=9) and females (n=8) performed three bouts of 30-s sprint exercise with 20 min rest between.Methods:Multiple blood samples were collected over time and muscle biopsy specimens were obtained at rest and 140 min after the last sprint.Results:Serum insulin increased by sprint exercise and more so in females than in males (gender (g) x time (t):P=0.04. In skeletal muscle, phosphorylation of Akt increased by 50% (t, P=0.001) and mTOR by 120% (t, P=0.002) independent of gender. The elevation in p70S6k phosphorylation was larger in females (g x t, P=0.03) and averaged 230% (P=0.006) as compared to 60% in males (P=0.04). Phosphorylation rpS6 increased by 660% over time independent of gender (t, P=0.003). Increase in phosphorylation of p70S6k was directly related to increase in serum insulin (r=0.68, P=0.004).Conclusion:It is concluded that repeated 30-s all out bouts of sprint exercise separated by 20 min of rest, increases Akt/mTOR signalling in skeletal muscle. Secondly, signalling downstream of mTOR was stronger in females than in males after sprint exercise indicated by increased phosphorylation of p70S6k.
      PubDate: 2011-12-26T22:40:26.6469-05:00
      DOI: 10.1111/j.1748-1716.2011.02404.x
  • The effects of early exercise on brain damage and recovery after focal
           cerebral infarction in rats
    • Authors: Fumiyo Matsuda; Harutoshi Sakakima, Yoshihiro Yoshida
      Abstract: Aim:  Exercise can be used to enhance neuroplasticity and facilitate motor recovery after a stroke in rats. We investigated whether treadmill running could reduce brain damage and enhance the expression of midkine (MK) and nerve growth factor (NGF), increase angiogenesis, and decrease the expression of caspase-3.Methods:  77 Wistar rats were split unto 3 experimental groups (ischemia-control: 36, ischemia-exercise: 36, sham-exercise: 5). Stroke was induced by 90 min left middle cerebral artery occlusion using an intraluminal filament. Beginning on the following day, the rats were made to run on a treadmill for 20 min once a day for a maximum of 28 consecutive days. Functional recovery after ischemia was assessed using the beam walking test and a neurological evaluation scale in all rats. Infarct volume, and the expression of MK, NGF, PECAM-1, and caspase-3 were evaluated at 1, 3, 5, 7, 14, and 28 days after the induction of ischemia.Results:  Over time motor coordination and neurological deficits improved more in the exercised group than in the non-exercised group. The infarct volume in the exercised group (12.4 ± 0.8%) subjected to treadmill running for 28 days was significantly decreased compared with that in the control group (19.8 ± 4.2%, P
      PubDate: 2010-08-17T12:31:06.031647-05:
      DOI: 10.1111/j.1748-1708.2010.02174.x
  • Effects of exercise training on adipogenesis of stromal-vascular fraction
           cells in rat epididymal white adipose tissue
    • Authors: Takuya Sakurai; Satohiro Endo, Daisuke Hatano, Junetsu Ogasawara, Takako Kizaki, Shuji Oh-ishi, Tetsuya Izawa, Hitoshi Ishida, Hideki Ohno
      Abstract: Aim:  Previous studies have shown that exercise training reduced white adipose tissue (WAT) mass compared to that in sedentary controls, and that the smaller mass contained fewer adipocytes. However, the effect of exercise training on adipogenesis is not completely clear. Therefore, we reexamined the effect of exercise training on adipocyte numbers in WAT and, if such an effect was found tested the adipogenic responses of stromal-vascular fraction (SVF) cells containing adipose tissue-derived stem cells (ADSC) in epididymal WAT from exercise-trained (TR) rats.Methods:  Wistar male rats were divided into two groups: control (C) and TR. The TR rats were subjected to exercise on a treadmill for 9 weeks. SVF cells containing ADSC were separated from epididymal WAT by centrifugation. Expression of adipocyte differentiation-related genes and adipogenesis of SVF cells were examined.Results:  In SVF cells of TR rats, the expression of peroxisome proliferator-activated receptor γ (PPARγ) and that of PPARγ target lipogenic genes were dramatically downregulated, whereas that of preadipocyte factor-1 gene was significantly upregulated. Lipid accumulation in SVF cells of TR rats after the induction of adipocyte differentiation was significantly suppressed in comparison to that of C rats. Moreover, increased expression of hypoxia inducible factor-1α (HIF-1α) protein was observed in SVF cells of TR rats. Pretreatment of YC-1, a potent HIF-1α inhibitor, in SVF cells of TR rats restored adipogenesis.Conclusion:  These results suggest that exercise training suppresses the ability of SVF cells to differentiate into adipocytes, and that underlying mechanisms involve the upregulation of HIF-1α expression.
      PubDate: 2010-06-28T00:00:00-05:00
      DOI: 10.1111/j.1748-1708.2010.02159.x
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