Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function
Mice with myocyte deletion of vitamin D receptor have sarcopenia and impaired muscle function
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DOI：
10.1002/jcsm.12460
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发表时间：
2019-12-01
影响因子：
8.9
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.
背景：维生素D缺乏与肌肉无力和跌倒有关，这一点早已被认识到。维生素D受体(VDR)在正常肌肉中含量很低。维生素D是否对肌肉功能起直接作用尚不清楚，也是一个激烈争论的话题。肌细胞特异性的VDR缺失将为回答这个问题提供一种策略。方法将人骨骼肌动蛋白-Cre小鼠与VDR小鼠杂交，获得肌细胞特异性维生素D受体(MVDR)缺失小鼠。结果与全身VDR基因敲除小鼠不同，mVDR小鼠具有正常的体型。MVDR显示出明显的肌肉表型，表现为瘦质量比例降低(70%比78%)，自主车轮跑距离减少(22%，P=0.009)，平均跑步速度降低，握力降低(测试时年龄不同，减少7%-16%)。随着自愿运动的减少和瘦体重的减少，mVDR的脂肪比例从13%增加到20%。令人惊讶的是，他们的肌肉纤维直径略有增加，角状纤维和中央核的存在表明正在进行重塑。然而，纤维类型没有明显的变化，肌肉纤维化也没有增加。VDR是一种转录调节因子，从骨骼肌提取的RNA中检测了候选基因表达的变化。生肌基因表达发生改变，细胞周期基因cyClinD1、D2、D3及细胞周期蛋白依赖性蛋白依赖性蛋白激酶CDK-2、CDK-4表达降低。钙调节基因肌浆/内质网钙ATPase(SERCA)、Serca2b和Serca3表达降低，Calbindin基因表达降低。结论心肌细胞功能需要维生素D信号转导。尽管肌肉中通常存在低水平的VDR蛋白，但删除肌细胞VDR对肌肉的大小和力量有重要影响。维持正常的维生素D信号是防止肌肉功能和大小丧失的一个有用的策略。
Background It has long been recognized that vitamin D deficiency is associated with muscle weakness and falls. Vitamin D receptor (VDR) is present at very low levels in normal muscle. Whether vitamin D plays a direct role in muscle function is unknown and is a subject of hot debate. Myocyte-specific deletion of VDR would provide a strategy to answer this question.Methods Myocyte-specific vitamin D receptor (mVDR) null mice were generated by crossing human skeletal actin-Cre mice with floxed VDR mice. The effects of gene deletion on the muscle phenotype were studied in terms of body tissue composition, muscle tissue histology, and gene expression by real-time PCR.Results Unlike whole-body VDR knockout mice, mVDR mice showed a normal body size. The mVDR showed a distinct muscle phenotype featuring reduced proportional lean mass (70% vs. 78% of lean mass), reduced voluntary wheel-running distance (22% decrease, P = 0.009), reduced average running speed, and reduced grip strength (7-16% reduction depending on age at testing). With their decreased voluntary exercise, and decreased lean mass, mVDR have increased proportional fat mass at 20% compared with 13%.Surprisingly, their muscle fibres showed slightly increased diameter, as well as the presence of angular fibres and central nuclei suggesting ongoing remodelling. There were, however, no clear changes in fibre type and there was no increase in muscle fibrosis. VDR is a transcriptional regulator, and changes in the expression of candidate genes was examined in RNA extracted from skeletal muscle. Alterations were seen in myogenic gene expression, and there was decreased expression of cell cycle genes cyclin D1, D2, and D3 and cyclin-dependent kinases Cdk-2 and Cdk-4. Expression of calcium handling genes sarcoplasmic/endoplasmic reticulum calcium ATPases (SERCA) Serca2b and Serca3 was decreased and Calbindin mRNA was lower in mVDR muscle.Conclusions This study demonstrates that vitamin D signalling is needed for myocyte function. Despite the low level of VDR protein normally found muscle, deleting myocyte VDR had important effects on muscle size and strength. Maintenance of normal vitamin D signalling is a useful strategy to prevent loss of muscle function and size.