Vitamin D Receptor Ablation and Vitamin D Deficiency Result in Reduced Grip Strength, Altered Muscle Fibers, and Increased Myostatin in Mice
Vitamin D Receptor Ablation and Vitamin D Deficiency Result in Reduced Grip Strength, Altered Muscle Fibers, and Increased Myostatin in Mice
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DOI：
10.1007/s00223-015-0054-x
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发表时间：
2015-12-01
影响因子：
4.2
通讯作者：
Gunton, Jenny E.
中科院分区：
文献类型：
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作者：
Girgis, Christian M.;Cha, Kuan Minn;Gunton, Jenny E.
维生素D缺乏与肌肉无力、疼痛和萎缩有关。血清维生素D可以预测肌肉力量和与年龄相关的肌肉变化。然而，维生素D影响骨骼肌的确切机制尚不清楚。为了解决这个问题，本研究表征了维生素D受体缺失（VDRKO）或饮食引起的维生素D缺乏症小鼠的肌肉表型和基因表达。VDRKO和维生素d缺乏小鼠的握力明显弱于对照组。虚弱分别随缺乏维生素D的年龄和持续时间而加重。组织学评估显示，VDRKO小鼠的肌纤维明显变小，并表现出高核性。Real-time PCR还显示，VDRKO小鼠肌肉发育发生变化，肌肉生成调节因子（MRFs）失调，股四头肌肌肉生长抑制素增加（2倍）。维生素d缺乏的小鼠也表现出肌肉生长抑制素和萎缩标志物e3 -泛素连接酶MuRF1的增加。作为握力弱的潜在解释，两组小鼠编码钙处理和肌内质网钙转运atp酶（Serca）通道的基因下调。这是通过直接测试排除钙、镁和磷酸盐混淆的VDRKO和维生素d缺乏小鼠的强度、形态和基因表达变化的第一个报告。虽然在早期的体外工作中提出，但这项研究是第一次报道维生素D，肌肉生长抑制素和肌肉质量调节之间的体内关联。这些发现支持了维生素D在肌肉功能中的直接作用，并证实了早期关于该组织中存在VDR的研究。
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.