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., Philp, A., Tarum, J., Kadi, F., Andersen, D., Garcia, A. M., Smith, K., Gallagher, I. J., Szewczyk, N. J., Cleasby, M. 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