1α,25(OH)2D3 downregulates gene expression levels of muscle ubiquitin ligases MAFbx and MuRF1 in human myotubes
1α,25(OH)2D3 downregulates gene expression levels of muscle ubiquitin ligases MAFbx and MuRF1 in human myotubes
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DOI：
10.2220/biomedres.36.71
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发表时间：
2015-04-01
影响因子：
1.2
通讯作者：
Kitamura, Hidemitsu
中科院分区：
文献类型：
--
作者：
Hayakawa, Naohiko;Fukumura, Junko;Kitamura, Hidemitsu
涉及骨质疏松症患者的临床试验报告称，活化的维生素D-3（1 α，25（OH）（2）D-3，骨化三醇）可以通过作用于骨骼肌来防止跌倒。然而，1 α，25（OH）（2）D-3与骨骼肌肥大或萎缩相关的药理学机制仍知之甚少。因此，我们研究了人类肌管中几个相关基因表达的变化，以测试1 α，25（OH）（2）D-3是否影响骨骼肌的肥大和萎缩。用1 α，25（OH）（2）D-3处理的肌管增加了白细胞介素-6（IL-6）的表达，抑制了肿瘤坏死因子α（TNF-α）的表达，而参与肌肉肥大的胰岛素样生长因子-1（IGF-1）的表达不受影响。然而，1 α，25（OH）（2）D-3处理显著抑制肌肉萎缩F-box（MAFbx）和肌肉RING指1（MuRF 1）的表达，这些蛋白是参与肌肉萎缩的泛素连接酶。使用微阵列数据的通路分析表明，1 α，25（OH）（2）D-3通过抑制磷脂酰肌醇3-激酶（PI 3 K）/AKT信号通路中蛋白磷酸酶2（PP 2A）（一种作用于AKT-1的磷酸酶）的表达上调AKT-1，从而抑制泛素连接酶的表达。因此，本研究表明，1 α，25（OH）（2）D-3可能对骨骼肌中MAFbx和MuRF 1的表达具有抑制作用，并对骨质疏松症患者的肌肉降解具有抑制作用。
Clinical trials involving in patients with osteoporosis have reported that activated vitamin D-3 (1 alpha,25(OH)(2)D-3, calcitriol) can prevent falling by acting on the skeletal muscles. However, pharmacological mechanisms of 1 alpha,25(OH)(2)D-3 with respect to skeletal muscle hypertrophy or atrophy are still poorly understood. Therefore, we examined changes in the expression of several related genes in human myotubes to test whether 1 alpha,25(OH)(2)D-3 influences hypertrophy and atrophy of skeletal muscle. Myotubes treated with 1 alpha,25(OH)(2)D-3 increased interleukin-6 (IL-6) expression and inhibited expression of tumor necrosis factor alpha (TNF-alpha), whereas the expression of insulin-like growth factor-1 (IGF-1) that is involved in muscle hypertrophy was not affected. However, 1 alpha,25(OH)(2)D-3 treatment significantly inhibited the expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1), ubiquitin ligases involved in muscle atrophy. The analysis of pathways using microarray data suggested that 1 alpha,25(OH)(2)D-3 upregulates AKT-1 by inhibiting the expression of protein phosphatase 2 (PP2A), a phosphatase acting on AKT-1, in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, thereby inhibiting the expression of ubiquitin ligases. Thus, this study showed that 1 alpha,25(OH)(2)D-3 might have an inhibitory effect on the expression of MAFbx and MuRF1 in skeletal muscle and a suppressive effect on muscle degradation in patients with osteoporosis.