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The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo

Bass, Joseph J. (författare)
MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK
Kazi, Abid A. (författare)
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
Deane, Colleen S. (författare)
Department of Sport and Health Sciences, University of Exeter, Exeter, UK; Living Systems Institute, University of Exeter, Stocker Road, Exeter, UK
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Nakhuda, Asif (författare)
MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK
Ashcroft, Stephen P. (författare)
School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK
Brook, Matthew S. (författare)
MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK
Wilkinson, Daniel J. (författare)
MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK
Phillips, Bethan E. (författare)
MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK
Philp, Andrew (författare)
School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK; Mitochondrial Metabolism & Ageing Laboratory, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Medical School, UNSW Medicine, UNSW Sydney, Sydney, Australia
Tarum, Janelle (författare)
School of Health Sciences, Örebro University, Örebro, Sweden
Kadi, Fawzi, 1970- (författare)
Örebro universitet,Institutionen för hälsovetenskaper
Andersen, Ditte (författare)
Molecular Physiology of Diabetes Laboratory, Dept. of Comparative Biomedical Sciences, Royal Veterinary College, UK
Garcia, Amadeo Muñoz (författare)
Institute of Metabolism and Systems Research, The University of Birmingham, Birmingham, UK; Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Metabolism in Translational Research, Maastricht University, Maastricht, The Netherlands
Smith, Ken (författare)
MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK
Gallagher, Iain J. (författare)
Physiology, Exercise and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, Stirling, UK
Szewczyk, Nathaniel J. (författare)
MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK
Cleasby, Mark E. (författare)
Molecular Physiology of Diabetes Laboratory, Dept. of Comparative Biomedical Sciences, Royal Veterinary College, UK
Atherton, Philip J. (författare)
MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK
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 (creator_code:org_t)
John Wiley & Sons, 2021
2021
Engelska.
Ingår i: Journal of Physiology. - : John Wiley & Sons. - 0022-3751 .- 1469-7793. ; 599:3, s. 963-979
Relaterad länk:
https://doi.org/10.1...
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https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • KEY POINTS:Reduced vitamin D receptor (VDR) expression prompts skeletal muscle atrophy.Atrophy occurs through catabolic processes, namely the induction of autophagy, while anabolism remains unchanged.In response to VDR-KD mitochondrial function and related gene-set expression is impaired.In vitro VDR knockdown induces myogenic dysregulation occurring through impaired differentiation.These results highlight the autonomous role the VDR has within skeletal muscle mass regulation.Objective: Vitamin-D deficiency is estimated to affect ∼40% of the world's population and has been associated with impaired muscle maintenance. Vitamin-D exerts its actions through the Vitamin-D-receptor (VDR), the expression of which was recently confirmed in skeletal muscle, and its down-regulation is linked to reduced muscle mass and functional decline. To identify potential mechanisms underlying muscle atrophy, we studied the impact of VDR knockdown (KD) on mature skeletal muscle in vivo, and myogenic regulation in vitro in C2C12 cells.Methods: Male Wistar rats underwent in vivo electrotransfer (IVE) to knock down the VDR in hind-limb tibialis anterior (TA) muscle for 10 days. Comprehensive metabolic and physiological analysis was undertaken to define the influence loss of the VDR on muscle fibre composition, protein synthesis, anabolic and catabolic signalling, mitochondrial phenotype, and gene expression. Finally, in vitro lentiviral transfection was used to induce sustained VDR-KD in C2C12 cells to analyse myogenic regulation.Results: Muscle VDR-KD elicited atrophy through a reduction in total protein content, resulting in lower myofibre area. Activation of autophagic processes was observed, with no effect upon muscle protein synthesis or anabolic signalling. Furthermore, RNA-Seq analysis identified systematic down-regulation of multiple mitochondrial respiration related protein and genesets. Finally, in vitro VDR-knockdown impaired myogenesis (cell cycling, differentiation and myotube formation).Conclusion: Taken together, these data indicate a fundamental regulatory role of the VDR in the regulation of myogenesis and muscle mass; whereby it acts to maintain muscle mitochondrial function and limit autophagy.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

Nyckelord

Atrophy
metabolism
skeletal muscle
vitamin D

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