The era of vitamin D as solely a regulator of bone and mineral homeostasis is long-gone. Recent evidence suggests vitamin D to be implicated in numerous chronic diseases and adverse health conditions, including those related to skeletal muscle. In fact, muscle weakness and pain are prominent features of vitamin D deficiency that respond to replacement therapy. It has been shown that vitamin D receptors (VDRs) are present in human skeletal muscle, but the precise mechanisms through which vitamin D exerts its effects in muscle are unclear.

It has been previously demonstrated that culturing muscle cells with vitamin D leads to marked cell growth associated with an inhibition of myostatin (the gate-keeper for growth, if you will). More recently, a pilot study in older women with vitamin D deficiency has shown repletion to increase intramuscular VDR expression and muscle fiber size. However, in vivo data concerning the direct effects of the VDR in muscle function are lacking. Thus, in order to examine the effect of vitamin D deficiency and the deletion of the VDR on grip strength, muscle bulk, fiber size, and gene expression, Girgis et al conducted two relatively simple experiments, each involving two groups of mice. 

In one experiment, the effects of complete abolition of the VDR were assessed using whole-body VDR knockout mice (VDRKO) and compared to healthy normal mice (control) for 3 months. Importantly, to isolate the direct effects of not having VDRs, the VDRKO were fed “rescue chow” that contained extra calcium, phosphorous, and vitamin D that normalized their blood mineral levels that would otherwise be out-of-whack.

In the second experiment, the effects of “normal” vitamin D deficiency were assessed by comparing healthy mice fed a vitamin D deficient (VDD) or replete (control) diet from 3-24 weeks of age. Similar to the rescue chow, the vitamin D deficient chow contained extra calcium, magnesium, and phosphorous to prevent mineral imbalances from the vitamin D deficiency and thus help to isolate the effects of a lack of vitamin D signaling.

The results were anything but ambiguous, with the VDRKO and VDD mice demonstrating a significant 48% and 25% less strength, respectively, than their controls at the end of the experiments. Additionally, the VDRKO mice had significantly less muscle mass in absolute terms and as a percentage of bodyweight and smaller muscle fibers, all without histologic changes that would indicate fiber remodeling and regeneration. In contrast, there were no differences between the VDD and control mice in muscle mass or fiber size.

The stark differences in muscle mass of the VDRKO mice are at least partially explained by gene expression. Myogenic regulatory factors MyoD and Myf5 were both significantly increased, consistent with their impaired muscle development and maturity, and the expression of Myostatin was more than 2-fold greater, easily explaining the substantial reduction in fiber size and muscle mass seen in these mice. The VDD mice also experienced a significant increase of Myostatin, albeit to a lesser extent than the VDRKO mice, which was associated with a significant increase in MuRF1, suggesting upregulation of atrophy pathways in the muscles.

Both VDRKO and VDD mice showed significant reductions in the expression of genes involved in intramuscular calcium handling, which could potentially result in impaired muscle contraction and may thus explain the reduced strength observed in the VDD mice despite no differences in muscle mass.

So I should start loading up on sunlight and vitamin D supplements, right? I take no issue with the former, but the last thing this study suggests is that supplementing vitamin D will do anything. This study did not in any way look at the effects of having a vitamin D status at various points within the normal range. Rather, it looked at the impact of being vitamin D deficient, brought on by two different mechanisms, while correcting for associated biochemical abnormalities. Therefore, this is the first study to conclude direct effects of vitamin D deficiency.

Interestingly, the greatest deficits in muscle mass and function were observed in mice subject to congenital ablation of the VDR, which strongly supports the notion for a developmental role of vitamin D signaling. In contrast, the diet-induced vitamin D deficient mice were allowed to mature before feeding of the experimental diet and only showed modest changes in atrophy-related gene expression with no observable changes in muscle mass or function. Thus, a longer duration of vitamin D deficiency may be necessary to produce observable changes in muscle histology when started after early growth development. Alternatively, perhaps the normalized mineral levels in these mice muted the overt development of muscle wasting from vitamin D deficiency.

Notwithstanding the fact that this research was conducted in mice, the takeaway is humble but vital, avoid vitamin D deficiency, especially during childhood when development is at its peak.