Background Vitamin D is an essential nutrient in musculoskeletal function; however, its relationship to sarcopenia remains ambiguous, and the mechanisms and targets of vitamin D activity have not been elucidated. This study aimed to clarify the role of vitamin D in mature skeletal muscle and its relationship with sarcopenia. Methods This epidemiological study included 1653 community residents who participated in both the fifth and seventh waves of the National Institute for Longevity Sciences, Longitudinal Study of Aging and had complete background data. Participants were classified into two groups: vitamin D‐deficient (serum 25‐hydroxyvitamin D < 20 ng/mL) and non‐deficient (serum 25‐hydroxyvitamin D ≥ 20 ng/mL); they underwent propensity‐score matching for background factors (age, sex, height, weight, comorbidities, smoker, alcohol intake, energy intake, vitamin D intake, steps, activity, season and sarcopenia). Changes in muscle strength and mass over the 4‐year period were compared. For basic analysis, we generated Myf6CreERT2 Vitamin D Receptor (VDR)‐floxed (VdrmcKO) mice with mature muscle fibre‐specific vitamin D receptor knockout, injected tamoxifen into 8‐week‐old mice and analysed various phenotypes at 16 weeks of age. Results Grip strength reduction was significantly greater in the deficient group (−1.55 ± 2.47 kg) than in the non‐deficient group (−1.13 ± 2.47 kg; P = 0.019). Appendicular skeletal muscle mass reduction did not differ significantly between deficient (−0.05 ± 0.79 kg) and non‐deficient (−0.01 ± 0.74 kg) groups (P = 0.423). The incidence of new cases of sarcopenia was significantly higher in the deficient group (15 vs. 5 cases; P = 0.039). Skeletal muscle phenotyping of VdrmcKO mice showed no significant differences in muscle weight, myofibre percentage or myofibre cross‐sectional area; however, both forelimb and four‐limb muscle strength were significantly lower in VdrmcKO mice (males: forelimb, P = 0.048; four‐limb, P = 0.029; females: forelimb, P < 0.001; four‐limb, P < 0.001). Expression profiling revealed a significant decrease in expression of sarcoendoplasmic reticulum Ca2+‐ATPase (SERCA) 1 (P = 0.019) and SERCA2a (P = 0.049) genes in the VdrmcKO mice. In contrast, expression of non‐muscle SERCA2b and myoregulin genes showed no changes. Conclusions Vitamin D deficiency affects muscle strength and may contribute to the onset of sarcopenia. Vitamin D‐VDR signalling has minimal influence on the regulation of muscle mass in mature myofibres but has a significant influence on muscle strength.
Vitamin D, a fat-soluble vitamin, is an important nutrient for tissue homeostasis and is recently gaining attention for its role in sarcopenia. Although several studies have focused on the role of vitamin D in muscle homeostasis, the molecular mechanism underlying its action on skeletal muscle remains unclear. This study investigated the role of vitamin D in myogenesis and muscle fiber maintenance in an immortalized mouse myogenic cell line. A high concentration of active vitamin D, 1α,25(OH)2D3, decreased the expression of myogenic regulatory factors (MRFs), myf5 and myogenin in proliferating myoblasts. In addition, high concentration of vitamin D reduced myoblast-to-myoblast and myoblast-to-myotube fusion through the inhibition of Tmem8c (myomaker) and Gm7325 (myomerger), which encode muscle-specific fusion-related micropeptides. A similar inhibitory effect of vitamin D was also observed in immortalized human myogenic cells. A high concentration of vitamin D also induced hypertrophy of multinucleated myotubes by stimulating protein anabolism. The results from this study indicated that vitamin D had both positive and negative effects on muscle homeostasis, such as in muscle regeneration and myofiber maintenance. Elderly individuals face a higher risk of falling and suffering fractures; hence, administration of vitamin D for treating fractures in the elderly could actually promote fusion impairment and, consequently, severe defects in muscle regeneration. Therefore, our results suggest that vitamin D replacement therapy should be used for prevention of age-related muscle loss, rather than for treatment of sarcopenia.
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