Overexpression of the vitamin D receptor (VDR) induces skeletal muscle hypertrophy

Abstract

Objective 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. Methods 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 (D 2 O) 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. 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., 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. Conclusion 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.

The Positive Impact of Vitamin D on Glucocorticoid-Dependent Skeletal Muscle Atrophy

“…Our results show that in DEX-induced atrophy rats, SOL muscle is sparing in both absolute ( Figure 5 A) and relative values ( Figure 6 A). In summary, the main explanation for such a massive decrease in vitamin D concentration with partial protection against atrophy is the supposition that skeletal muscle cells overexpress VDR under both atrophy and hypertrophy conditions [ 54 ].…”

Increased 1,25(OH)2-Vitamin D Concentrations after Energy Restriction Are Associated with Changes in Skeletal Muscle Phenotype

“…The action of 1,25(OH) 2 -vitamin D on muscle is likely to be mediated by interaction with the vitamin D receptor (VDR). VDR over-expression has been reported to promote muscle anabolism [ 53 ], while VDR knockouts show muscle atrophy [ 54 ]. The 1,25(OH) 2 -vitamin D stimulates myogenesis through both genomic and non-genomic VDR-mediated mechanisms.…”

Sarcopenia in Inflammatory Bowel Disease: A Narrative Overview

“…Significantly, vitamin D deficiency is associated with sarcopenia in older people [ 46 ]. Whilst the specific mechanisms whereby vitamin D deficiency contributes to muscle loss are unclear; it is likely that the vitamin D receptor (VDR) plays a role via changes in anabolic signaling, muscle protein synthesis and translational efficacy [ 53 , 54 ]. Aside from the direct actions on skeletal muscle, the VDR is also known to impact mitochondrial function, whereby depletion of the VDR results in reduced oxidative phosphorylation output [ 55 ].…”