Vitamin D Receptor Ablation and Vitamin D Deficiency Result in Reduced Grip Strength, Altered Muscle Fibers, and Increased Myostatin in Mice

Abstract

Vitamin D deficiency is associated with muscle weakness, pain, and atrophy. Serum vitamin D predicts muscle strength and age-related muscle changes. However, precise mechanisms by which vitamin D affects skeletal muscle are unclear. To address this question, this study characterizes the muscle phenotype and gene expression of mice with deletion of vitamin D receptor (VDRKO) or diet-induced vitamin D deficiency. VDRKO and vitamin D-deficient mice had significantly weaker grip strength than their controls. Weakness progressed with age and duration of vitamin D deficiency, respectively. Histological assessment showed that VDRKO mice had muscle fibers that were significantly smaller in size and displayed hyper-nuclearity. Real-time PCR also indicated muscle developmental changes in VDRKO mice with dysregulation of myogenic regulatory factors (MRFs) and increased myostatin in quadriceps muscle (>2-fold). Vitamin D-deficient mice also showed increases in myostatin and the atrophy marker E3-ubiqutin ligase MuRF1. As a potential explanation for grip strength weakness, both groups of mice had down-regulation of genes encoding calcium-handling and sarco-endoplasmic reticulum calcium transport ATPase (Serca) channels. This is the first report of reduced strength, morphological, and gene expression changes in VDRKO and vitamin D-deficient mice where confounding by calcium, magnesium, and phosphate have been excluded by direct testing. Although suggested in earlier in vitro work, this study is the first to report an in vivo association between vitamin D, myostatin, and the regulation of muscle mass. These findings support a direct role for vitamin D in muscle function and corroborate earlier work on the presence of VDR in this tissue.

Vitamin D3 intake modulates diaphragm but not peripheral muscle force in young mice

“…Secondly, our dietary intervention was fairly short-term (6 wk) compared with prior studies (where deficiency was established for Ն2 mo). Time-related effects of deficiency on peripheral muscle performance are supported by studies in which mice that received a vitamin D-depleted diet for 3 mo showed a greater deficit in grip strength than mice that received a vitamin D-depleted diet for only 2 mo (13). Lastly, we studied the EDL instead of the soleus or epitrochlearis that were studied by others (27,32).…”

“…Doucet et al demonstrated phosphorylation of Akt/ FOXO in nonhypoxemic COPD patients with muscle wasting compared with COPD patients with preserved muscle mass (8a). Recent studies from Girgis et al (13) showed that skeletal muscle from vitamin D receptor knockout or vitamin D-deficient mice exhibits simultaneous upregulation of myostatin (growth inhibition) and myogenic markers MyoD and Myf 5 vs. control mice. Similarly, models of insulin resistance also exhibit aberrant or hyperactive mTOR signaling under fasted conditions, as does aging muscle (10,37).…”

Altered bone‐regulating myokine expression in skeletal muscle Of Duchenne muscular dystrophy mouse models

“…Although not yet tested in DMD, emerging evidence shows that vitamin D deficiency/supplementation influences the expression/secretion of certain myokines. VDR ablation and vitamin D deficiency increased MSTN expression; vitamin D supplementation inhibited its expression in C2C12 skeletal muscle cells, and VDR activator usage is related to lower serum MSTN levels in patients undergoing peritoneal dialysis . A recent study showed that vitamin D supplementation inhibited IL‐6 surge in tail‐suspended mice (disuse‐induced muscle atrophy model); and serum vitamin D concentration was significantly and negatively correlated with the serum IL‐6 in infertile women with tubal factor infertility .…”

Serum Vitamin D and Age-Related Muscle Loss in Afro-Caribbean Men: The Importance of Age and Diabetic Status

“…Vitamin D may regulate insulin sensitivity in skeletal muscle (25), possibly by upregulating insulin receptors expression (26), and enhancing the insulin signaling pathway (27). Vitamin D may alter the serum levels of muscle growth factors and atrophy markers as reported in an animal study (28). Furthermore, it has been suggested that vitamin D may directly contribute to myoblast proliferation and differentiation in animal (29), and human cells (30) by regulating gene transcription via vitamin D receptor (VDR) signaling pathway.…”