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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.; Kazi, Abid A.; Deane, Colleen S.; Nakhuda, Asif; Ashcroft, Stephen P.; Brook, Matthew S.; Wilkinson, Daniel J.; Phillips, Bethan E.; Philp, Andrew; Tarum, Janelle; Kadi, Fawzi; Andersen, Ditte; Garcia, Amadeo Mu�oz; Smith, Ken; Gallagher, Iain J.; Szewczyk, Nathaniel J.; Cleasby, Mark E.; Atherton, Philip J.

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Authors

JOSEPH BASS Joseph.Bass@nottingham.ac.uk
Assistant Professor (Physiology and Endocrinology)

Abid A. Kazi

Colleen S. Deane

Asif Nakhuda

Stephen P. Ashcroft

BETH PHILLIPS beth.phillips@nottingham.ac.uk
Professor of Translational Physiology

Andrew Philp

Janelle Tarum

Fawzi Kadi

Ditte Andersen

Amadeo Mu�oz Garcia

KENNETH SMITH KEN.SMITH@NOTTINGHAM.AC.UK
Professor of Metabolic Mass Spectrometry

Iain J. Gallagher

Nathaniel J. Szewczyk

Mark E. Cleasby

PHILIP ATHERTON philip.atherton@nottingham.ac.uk
Professor of Clinical, metabolic & Molecular Physiology



Abstract

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 ∼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 10days. 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.

Citation

Bass, J. J., Kazi, A. A., Deane, C. S., Nakhuda, A., Ashcroft, S. P., Brook, M. S., …Atherton, P. J. (2021). The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo. Journal of Physiology, 599(3), 963-979. https://doi.org/10.1113/JP280652

Journal Article Type Article
Acceptance Date Nov 25, 2020
Online Publication Date Dec 1, 2020
Publication Date Feb 1, 2021
Deposit Date Dec 4, 2020
Publicly Available Date Dec 4, 2020
Journal The Journal of Physiology
Print ISSN 0022-3751
Electronic ISSN 1469-7793
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 599
Issue 3
Pages 963-979
DOI https://doi.org/10.1113/JP280652
Keywords Physiology
Public URL https://nottingham-repository.worktribe.com/output/5100301
Publisher URL https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP280652

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