Reduced nuclear translocation of serum response factor is associated with skeletal muscle atrophy in a cigarette smoke-induced mouse model of COPD.
Reduced nuclear translocation of serum response factor is associated with skeletal muscle atrophy in a cigarette smoke-induced mouse model of COPD.
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DOI：
10.2147/copd.s109243
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发表时间：
2017
影响因子：
2.8
通讯作者：
Zhong N
中科院分区：
文献类型：
--
作者：
Ma R;Gong X;Jiang H;Lin C;Chen Y;Xu X;Zhang C;Wang J;Lu W;Zhong N
骨骼肌萎缩和功能障碍是慢性阻塞性肺疾病（COPD）的常见并发症。然而，潜在的分子机制仍然难以捉摸。血清反应因子（Serum response factor，SRF）是一种在心肌细胞分化和生长中起关键作用的转录因子。在这项研究中，我们建立了一个小鼠慢性阻塞性肺疾病模型吸烟（CS）暴露24周，具有明显的病理生理变化，包括气道阻力增加，肺泡扩大，骨骼肌萎缩。COPD小鼠股四头肌中SRF上游调节因子、横纹肌Rho信号激活因子（STARS）和ras同源基因家族成员A（RhoA）的水平降低。同时，SRF的核定位随着其在细胞质中的积累而沿着减少。靶肌肉特异性基因Igf 1下调。这些结果表明，CS是COPD发病的主要原因之一，其导致COPD相关的骨骼肌萎缩与SRF核转位减少，从而下调与肌肉生长和营养相关的SRF靶基因密切相关。STARS/RhoA信号通路可能通过影响SRF亚细胞分布而促进这一过程。
Skeletal muscle atrophy and dysfunction are common complications in the chronic obstructive pulmonary disease (COPD). However, the underlying molecular mechanism remains elusive. Serum response factor (SRF) is a transcription factor which is critical in myocyte differentiation and growth. In this study, we established a mouse COPD model induced by cigarette smoking (CS) exposure for 24 weeks, with apparent pathophysiological changes, including increased airway resistance, enlarged alveoli, and skeletal muscle atrophy. Levels of upstream regulators of SRF, striated muscle activator of Rho signaling (STARS), and ras homolog gene family, member A (RhoA) were decreased in quadriceps muscle of COPD mice. Meanwhile, the nucleic location of SRF was diminished along with its cytoplasmic accumulation. There was a downregulation of the target muscle-specific gene, Igf1. These results suggest that the CS is one of the major causes for COPD pathogenesis, which induces the COPD-associated skeletal muscle atrophy which is closely related to decreasing SRF nucleic translocation, consequently downregulating the SRF target genes involved in muscle growth and nutrition. The STARS/RhoA signaling pathway might contribute to this course by impacting SRF subcellular distribution.