PMID- 33258480 OWN - NLM STAT- MEDLINE DCOM- 20210412 LR - 20240331 IS - 1469-7793 (Electronic) IS - 0022-3751 (Print) IS - 0022-3751 (Linking) VI - 599 IP - 3 DP - 2021 Feb TI - The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo. PG - 963-979 LID - 10.1113/JP280652 [doi] AB - 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-knockdown 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. ABSTRACT: Vitamin D deficiency is estimated to affect approximately 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. 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. 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-sequencing 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). 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. CI - (c) 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. FAU - Bass, Joseph J AU - Bass JJ AUID- ORCID: 0000-0002-8236-681X AD - 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. FAU - Kazi, Abid A AU - Kazi AA AD - Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA. FAU - Deane, Colleen S AU - Deane CS AUID- ORCID: 0000-0002-2281-6479 AD - Department of Sport and Health Sciences, University of Exeter, Exeter, UK. AD - Living Systems Institute, University of Exeter, Exeter, UK. FAU - Nakhuda, Asif AU - Nakhuda A AD - 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. FAU - Ashcroft, Stephen P AU - Ashcroft SP AD - School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK. FAU - Brook, Matthew S AU - Brook MS AD - 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. FAU - Wilkinson, Daniel J AU - Wilkinson DJ AUID- ORCID: 0000-0001-8808-8243 AD - 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. FAU - Phillips, Bethan E AU - Phillips BE AD - 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. FAU - Philp, Andrew AU - Philp A AD - School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK. AD - Mitochondrial Metabolism & Ageing Laboratory, Diabetes and Metabolism Division, Garvan Institute of Medical Research, New South Wales, Australia. AD - St Vincent's Medical School, UNSW Medicine, UNSW, Sydney, Australia. FAU - Tarum, Janelle AU - Tarum J AD - School of Health Sciences, Orebro University, Orebro, Sweden. FAU - Kadi, Fawzi AU - Kadi F AUID- ORCID: 0000-0002-9831-0896 AD - School of Health Sciences, Orebro University, Orebro, Sweden. FAU - Andersen, Ditte AU - Andersen D AD - Molecular Physiology of Diabetes Laboratory, Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK. FAU - Garcia, Amadeo Munoz AU - Garcia AM AUID- ORCID: 0000-0002-8634-3244 AD - Institute of Metabolism and Systems Research, The University of Birmingham, Birmingham, UK. AD - Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Metabolism in Translational Research, Maastricht University, Maastricht, The Netherlands. FAU - Smith, Ken AU - Smith K AUID- ORCID: 0000-0001-8971-6635 AD - 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. FAU - Gallagher, Iain J AU - Gallagher IJ AUID- ORCID: 0000-0002-8630-7235 AD - Physiology, Exercise and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, Stirling, UK. FAU - Szewczyk, Nathaniel J AU - Szewczyk NJ AUID- ORCID: 0000-0003-4425-9746 AD - 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. FAU - Cleasby, Mark E AU - Cleasby ME AUID- ORCID: 0000-0003-1020-5264 AD - Molecular Physiology of Diabetes Laboratory, Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK. FAU - Atherton, Philip J AU - Atherton PJ AUID- ORCID: 0000-0002-7286-046X AD - 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. LA - eng GR - MR/P021220/1/MRC_/Medical Research Council/United Kingdom GR - MR/T026014/1/MRC_/Medical Research Council/United Kingdom GR - MR/J500495/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201224 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 0 (Receptors, Calcitriol) RN - 1406-16-2 (Vitamin D) SB - IM CIN - J Physiol. 2021 Apr;599(7):1955-1956. PMID: 33476041 MH - Animals MH - Male MH - Muscle Fibers, Skeletal MH - Muscle, Skeletal/pathology MH - Muscular Atrophy/genetics/pathology MH - Rats MH - Rats, Wistar MH - *Receptors, Calcitriol/genetics MH - Vitamin D MH - *Vitamin D Deficiency PMC - PMC7986223 OTO - NOTNLM OT - atrophy OT - metabolism OT - skeletal muscle OT - vitamin D EDAT- 2020/12/02 06:00 MHDA- 2021/04/13 06:00 PMCR- 2020/12/24 CRDT- 2020/12/01 08:37 PHST- 2020/08/12 00:00 [received] PHST- 2020/11/25 00:00 [accepted] PHST- 2020/12/02 06:00 [pubmed] PHST- 2021/04/13 06:00 [medline] PHST- 2020/12/01 08:37 [entrez] PHST- 2020/12/24 00:00 [pmc-release] AID - TJP14489 [pii] AID - 10.1113/JP280652 [doi] PST - ppublish SO - J Physiol. 2021 Feb;599(3):963-979. doi: 10.1113/JP280652. Epub 2020 Dec 24.