Novel insights into the autonomous role played by vitamin D receptor in the regulation of skeletal muscle mass

Skeletal muscles account for 40–50% of the whole-body mass in healthy individuals, and they contribute to a multitude of vital functions, such as in movement, postural support, breathing, thermogenesis and metabolism. The decline of skeletal muscle mass and function is a common feature observed in many pathological conditions, such as cancer, chronic obstructive pulmonary disease, type 2 diabetes, heart failure, chronic kidney disease, immobility, sepsis and neuromuscular diseases. The loss of skeletal muscle mass and function is also observed in sarcopenia, which often leads to frailty, falls and immobility associated with bed rest. The maintenance of skeletal muscle health is an important determinant of quality of life. Although the mechanisms underlying sarcopenia remain only partly understood, there is emerging evidence suggesting that vitamin D deficiency may play an important role in the decline of muscle function during ageing (Halfon et al. 2015). Vitamin D is a lipid-soluble secosteroid that plays important roles in numerous essential cellular and molecular functions, such as calcium and phosphate homeostasis that are essential for the maintainence of bone and muscle health. Vitamin D deficiency is currently a worldwide phenomenon that affects mostly older adults. Over the past two decades, there has been increasing evidence suggesting that either vitamin D deficiency or vitamin D receptor (VDR) mutation/deficiency are involved in the decline of muscle mass and function in the elderly. For instance, ageing is associated with a decrease in levels of intracellular 1,25-dihydroxyvitamin D receptor expression and serum 25-hydroxyvitamin D [25(OH)D] (Bischoff-Ferrari et al. 2004). Since the discovery of the VDR in skeletal muscle, there is an increasing body of literature suggesting that VDR signalling activated by vitamin D plays important roles in regulating numerous cellular process including protein synthesis and degradation (Dzik & Kaczor, 2019). However, the underlying mechanisms of these interactions within the context of regulating skeletal muscle mass are still not fully understood. In a recent study published in the Journal of Physiology, Bass et al. (2021) investigated the effects of VDR knockdown on skeletal muscle mass. To understand how VDR is linked to skeletal muscle mass, Bass and colleagues used a loss-of-function approach to characterize the role of VDR in 8-week-old male Wistar rats and in a C2C12 murine myoblast cell line. They provide interesting in vivo data indicating that VDR knockdown (KD) triggered skeletal muscle atrophy. Several mechanisms have been proposed to explain the nature of muscle atrophy, including decreased protein synthesis and increased protein degradation. Briefly, while the researchers did not observe a difference in the level of protein synthesis, they reported that numerous markers of autophagy, including the protein content of Cathepsin L, a lysosomal enzyme, and LC3B-II, a marker of autophagosome formation, were significantly increased in VDR-KD muscles when compared to contralateral leg. It is interesting to note that while most studies report an increase in the expression of muscle-specific ubiquitin E3 ligases, Atrogin-1 and MuRF-1, during muscle wasting, the authors reported a trend towards downregulation of both E3 ligases in response to the VDR-KD. The authors also reported increased gene expressions of Atg7, Atg5 and Ctsl. These data suggest that VDR-KD triggers an increase in autophagic activity. Moreover, the authors reported a trend towards decreased mitochondrial Complex I and IV protein contents in response to VDR-KD. Interestingly, findings from RNA-sequencing analysis indicated that VDR-KD downregulated various metabolic processes governed by mitochondria, such as the citric acid cycle (TCA) and ATP synthesis. Those data are consistent with recent reports from the same research group which suggested that VDR-KD in C2C12 myoblasts potentially induces mitochondrial dysfunction. Indeed, they demonstrated that VDR regulates skeletal muscle mitochondrial respiration in vitro (Ashcroft et al. 2020). Given that the current study by Bass and colleagues did not address the role of VDR in mediating mitochondrial function in vivo, future studies should address whether the observed changes in gene expression are associated with impaired mitochondrial ATP production, respiration, reactive oxygen species production and Ca2+ retention capacity. In their recent study, Bass and colleagues further evaluated the effects of in vitro VDR-KD and reported that silencing VDR in C2C12 myoblasts alters myogenesis by impairing cell cycle progression, proliferation, transition to differentiation and terminal differentiation. Indeed, flow cytometry and BrdU incorporation analyses indicated that VDR-KD attenuated myoblast proliferation, as indicated by an increase in the proportion of cells in G0–G1 cell cycle phase and reduction in DNA synthesis. Furthermore, VDR-KD greatly impaired terminal differentiation by inducing abnormal myotube formation, increased myonuclei and increased DNA contents. The findings that VDR-KD cells grown in serum-reduced medium have greater DNA contents relative to control cells, while protein and RNA contents are decreased, suggest DNA damage and genomic instability. Therefore, to gain a better understanding of how VDR regulates muscle cell cycle progression, proliferation and differentiation, future studies should be dedicated to performing gamma H2AX staining to evaluate if DNA repair mechanisms are actually affected by VDR-KD. Overall, these experimental data highlight the importance and previously unknown autonomous roles of VDR in maintaining skeletal muscle mass by potentially regulating autophagy. Linking impaired VDR function, muscle atrophy and induction of the autophagic programme in a pre-clinical model opens important avenues for future research into the mechanisms through which VDR regulates skeletal muscle mass. Understanding the potential role of VDR-mediated autophagy in various pathological conditions and the specific proteins involved in this pathway will have a major impact on identification of novel therapeutic targets for prevention and potential treatment of muscle dysfunction caused by vitamin D deficiency or impairments in VDR function. In these future experiments, it may be of interest to evaluate the modulatory role of VDR in the regulation of mitophagy (recycling of dysfunctional mitochondria by the autophagy pathway). The observation that VDR-KD had an effect on complex I (albeit not significant) may provide a clue towards this link, as inhibition of complex I is known to stimulate mitophagy. It is therefore tempting to speculate that VDR may play a modulatory role in skeletal muscle mitochondrial function by potentially controlling levels of mitophagy. Future studies may consider assessing autophagic flux to fully establish if the effect of VDR-KD is on increased autophagy or impaired/decreased lysosomal function. Besides evaluating autophagic flux, transgenic reporter mice designed for in vivo assessment of mitophagy such as Mito-QC mice and MitoTimer provide excellent tools for evaluating the potential role of VDR in regulating mitochondrial turnover by the autophagy pathway. A better understanding of the potential link between VDR and mitophagy would have important implications for the development of novel therapies for the treatment of various diseases associated with mitochondrial health. Moreover, the observation that VDR is required for both muscle cell cycle progression and transition to differentiation opens a new avenue for research into the autonomous role of VDR during muscle regeneration. Indeed, muscle satellite cell activation, proliferation, differentiation and fusion into new myofibres are critical processes for proper repair of injured muscles and for the maintenance of skeletal muscle mass and function throughout life. To fully evaluate the therapeutic potential of VDR, a pre-clinical aged animal model in which VDR is selectively overexpressed in satellite cells may be of great interest in future research on muscle regeneration. Performing RNA-sequencing analyses of muscles with VDR knockout and control muscles during satellite cell activation, proliferation, differentiation and fusion into myofibres will enable the researchers to gain a better understanding of the molecular mechanisms through which vitamin D signalling affects myoblast differentiation. These future investigations would greatly enhance our understanding of the autonomous role of the VDR during skeletal muscle development, health and regeneration. Finally, to bridge the gap between translational research and clinical practice, it is important to consider the relevance of the findings by Bass and colleagues and the proposed experiments highlighted in this letter from an evolutionary and historical perspective of vitamin D research and practice. The discovery of vitamin D as a secosteroid produced by skin in response to ultraviolet light exposure made it possible to directly link vitamin D deficiency to rickets, a disease that appeared in epidemic form during the industrial revolution. Furthermore, with the advancement of science and technology, the essential role of vitamin D in maintaining overall health has been more easily understood at the cellular level. To understand vitamin D and VDR function from a therapeutic point of view, future research needs to consider the evolutionary differences between VDR structure and function within nocturnal rodent models and diurnal humans. The roles of VDR are likely to differ between rodents and humans because the structure and function of VDR reflect the evolutionary life history of the species in question. The authors have no conflicts of interest, financial or otherwise, to declare. All authors: conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. Tomer Jordi Chaffer was supported by an Honours Summer Research Award from Acadia University and currently holds an NSHRF Scotia Scholars Award. Jean-Philippe Leduc-Gaudet was supported by a CIHR Vanier Fellowship and currently holds an RI-MUHC Fellowship. The authors apologise for not citing all relevant articles due to reference limitations of the Journal Club format.

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