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Over-expression of the vitamin D receptor (VDR) induces skeletal muscle hypertrophy

Bass, Joseph J.; Nakhuda, Asif; Deane, Colleen S.; Brook, Matthew S.; Wilkinson, Daniel J.; Phillips, Bethan E.; Philp, Andrew; Tarum, Janelle; Kadi, Fawzi; Andersen, Ditte; Garcia, Amadeo Muñoz; Smith, Ken; Gallagher, Iain J.; Szewczyk, Nathaniel J.; Cleasby, Mark E.; Atherton, Philip J.


Joseph J. Bass

Asif Nakhuda

Colleen S. Deane

Matthew S. Brook

Daniel J. Wilkinson

Bethan E. Phillips

Andrew Philp

Janelle Tarum

Fawzi Kadi

Ditte Andersen

Amadeo Muñoz Garcia

Ken Smith

Iain J. Gallagher

Nathaniel J. Szewczyk

Mark E. Cleasby

Philip J. Atherton


The Vitamin D receptor (VDR) has been positively associated with skeletal muscle mass, function and regeneration. Mechanistic studies have focused on the loss of the receptor, with in vivo whole-body knockout models demonstrating reduced myofibre size and function and impaired muscle development. To understand the mechanistic role upregulation of the VDR elicits in muscle mass/health, we studied the impact of VDR over-expression (OE) in vivo before exploring the importance of VDR expression upon muscle hypertrophy in humans.

Wistar rats underwent in vivo electrotransfer (IVE) to overexpress the VDR in the Tibialis anterior (TA) muscle for 10 days, before comprehensive physiological and metabolic profiling to characterise the influence of VDR-OE on muscle protein synthesis (MPS), anabolic signalling and satellite cell activity. Stable isotope tracer (D2O) techniques were used to assess sub-fraction protein synthesis, alongside RNA-Seq analysis. Finally, human participants underwent 20 wks of resistance exercise training, with body composition and transcriptomic analysis.

Muscle VDR-OE yielded total protein and RNA accretion, manifesting in increased myofibre area, i.e., hypertrophy. The observed increases in MPS were associated with enhanced anabolic signalling, reflecting translational efficiency (e.g., mammalian target of rapamycin (mTOR-signalling), with no effects upon protein breakdown markers being observed. Additionally, RNA-Seq illustrated marked extracellular matrix (ECM) remodelling, while satellite cell content, markers of proliferation and associated cell-cycled related gene-sets were upregulated. Finally, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise type training.

VDR-OE stimulates muscle hypertrophy ostensibly via heightened protein synthesis, translational efficiency, ribosomal expansion and upregulation of ECM remodelling-related gene-sets. Furthermore, VDR expression is a robust marker of the hypertrophic response to resistance exercise in humans. The VDR is a viable target of muscle maintenance through testable Vitamin D molecules, as active molecules and analogues.


Bass, J. J., Nakhuda, A., Deane, C. S., Brook, M. S., Wilkinson, D. J., Phillips, B. E., …Atherton, P. J. (2020). Over-expression of the vitamin D receptor (VDR) induces skeletal muscle hypertrophy. Molecular Metabolism, 101059.

Journal Article Type Article
Acceptance Date Jul 28, 2020
Publication Date Aug 7, 2020
Deposit Date Sep 7, 2020
Publicly Available Date Sep 7, 2020
Journal Molecular Metabolism
Publisher Elsevier
Peer Reviewed Peer Reviewed
Pages 101059
Public URL
Publisher URL


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