Spine Disease Research Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China.
J Bone Miner Res. 2022 Jan;37(1):121-136. doi: 10.1002/jbmr.4441. Epub 2021 Sep 29.
The nutritional level of vitamin D may affect musculoskeletal health. We have reported that vitamin D is a pivotal protector against tissue injuries by suppressing local renin-angiotensin system (RAS). This study aimed to explore the role of the vitamin D receptor (VDR) in the protection against muscle atrophy and the underlying mechanism. A cross-sectional study on participants (n = 1034) in Shanghai (China) was performed to analyze the association between vitamin D level and the risk of low muscle strength as well as to detect the circulating level of angiotensin II (Ang II). In animal studies, dexamethasone (Dex) was applied to induce muscle atrophy in wild-type (WT) and VDR-null mice, and the mice with the induction of muscle atrophy were treated with calcitriol for 10 days. The skeletal muscle cell line C2C12 and the muscle satellite cells were applied in in vitro studies. The increased risk of low muscle strength was correlated to a lower level of vitamin D (adjusted odds ratio [OR] 0.58) accompanied by an elevation in serum Ang II level. Ang II impaired the myogenic differentiation of C2C12 myoblasts as illustrated by the decrease in the area of myotubes and the downregulation of myogenic factors (myosin heavy chain [MHC] and myogenic differentiation factor D [MyoD]). The phenotype of muscle atrophy induced by Dex and Ang II was aggravated by VDR ablation in mice and in muscle satellite cells, respectively, and mediated by RAS and its downstream phosphatidylinositol 3-kinase/protein kinase B/forkhead box O1 (PI3K/Akt/FOXO1) signaling. Calcitriol treatment exhibited beneficial effects on muscle function as demonstrated by the increased weight-loaded swimming time, grip strength, and fiber area, and improved fiber type composition via regulating ubiquitin ligases and their substrates MHC and MyoD through suppressing renin/Ang II axis. Taken together, VDR protects against skeletal muscle atrophy by suppressing RAS. Vitamin D could be a potential agent for the prevention and treatment of skeletal muscle atrophy. © 2021 American Society for Bone and Mineral Research (ASBMR).
维生素 D 的营养水平可能会影响肌肉骨骼健康。我们已经报道过，维生素 D 通过抑制局部肾素-血管紧张素系统 (RAS) 来保护组织免受损伤，是一种关键的保护因子。本研究旨在探索维生素 D 受体 (VDR) 在防止肌肉萎缩中的作用及其潜在机制。对上海（中国）的 1034 名参与者进行了一项横断面研究，分析了维生素 D 水平与低肌肉力量风险之间的关系，并检测了血管紧张素 II (Ang II) 的循环水平。在动物研究中，用地塞米松 (Dex) 诱导野生型 (WT) 和 VDR 基因敲除 (KO) 小鼠发生肌肉萎缩，并在诱导肌肉萎缩后用骨化三醇治疗 10 天。体外研究应用 C2C12 成肌细胞和肌卫星细胞。结果发现，较低的维生素 D 水平与较低的肌肉力量风险相关（校正后的比值比 [OR] 0.58），同时血清 Ang II 水平升高。Ang II 降低了 C2C12 成肌细胞的成肌分化，表现为肌管面积减小和肌生成因子（肌球蛋白重链 [MHC] 和肌生成分化因子 D [MyoD]）表达下调。在 Dex 和 Ang II 诱导的肌肉萎缩中，VDR 缺失加剧了小鼠和肌卫星细胞的肌肉萎缩表型，其机制涉及 RAS 及其下游的磷脂酰肌醇 3-激酶/蛋白激酶 B/叉头框 O1 (PI3K/Akt/FOXO1) 信号通路。骨化三醇治疗通过抑制肾素/Ang II 轴，调节泛素连接酶及其底物 MHC 和 MyoD，对肌肉功能有有益作用，表现为增加负重游泳时间、握力和纤维面积，以及改善纤维类型组成。总之，VDR 通过抑制 RAS 来防止骨骼肌肉萎缩。维生素 D 可能是预防和治疗骨骼肌肉萎缩的潜在药物。
