Overexpression 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 Mu�oz; Smith, Ken; Gallagher, Iain J.; Szewczyk, Nathaniel J.; Cleasby, Mark E.; Atherton, Philip J.

Abstract

Objective
The Vitamin D receptor (VDR) has been positively associated with skeletal muscle mass, function and regeneration. Mechanistic studies have focused upon loss of the receptor, with in vivo whole-body knockout models demonstrating reduced myofiber 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.

Methods
Wistar rats underwent in vivo electrotransfer (IVE) to over-express the VDR in 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 resistance exercise training, with body composition and transcriptomic analysis.

Results
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. mTOR-signalling), with no effects upon protein breakdown markers being observed. Additionally, RNA-Seq illustrated marked extracellular matrix (ECM) remodeling, while satellite cell content, markers of proliferation and associated cell-cycled related gene-sets were up-regulated. Finally, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise type training.

Conclusion
VDR-OE stimulates muscle hypertrophy ostensibly via heightened protein synthesis, translational efficiency, ribosomal expansion and up-regulation 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 analogs.

Citation

Bass, J. J., Nakhuda, A., Deane, C. S., Brook, M. S., Wilkinson, D. J., Phillips, B. E., …Atherton, P. J. (2020). Overexpression of the vitamin D receptor (VDR) induces skeletal muscle hypertrophy. Molecular Metabolism, 42, Article 101059. https://doi.org/10.1016/j.molmet.2020.101059

• Journal Article Type: Article
• Acceptance Date: Jul 28, 2020
• Online Publication Date: Aug 7, 2020
• Publication Date: Dec 1, 2020
• Deposit Date: Aug 6, 2020
• Publicly Available Date: Sep 9, 2020
• Journal: Molecular Metabolism
• Electronic ISSN: 2212-8778
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 42
• Article Number: 101059
• DOI: https://doi.org/10.1016/j.molmet.2020.101059
• Keywords: Vitamin D; Skeletal Muscle; Metabolism; Exercise
• Public URL: https://nottingham-repository.worktribe.com/output/4814467
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2212877820301332