Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria, Australia.
Am J Physiol Cell Physiol. 2013 Aug 15;305(4):C414-26. doi: 10.1152/ajpcell.00421.2012. Epub 2013 May 29.
Skeletal muscle mass is regulated by sensing and transmitting extracellular mechanical stress signals to intracellular signaling pathways controlling protein synthesis and degradation. Striated muscle activator of Rho signaling (STARS) is a muscle-specific actin-binding protein that is sensitive to extracellular stress signals. STARS stimulates actin polymerization and influences serum response factor (SRF) and peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α transcription of genes involved in muscle growth, structure, and contraction. The role of STARS in skeletal muscle cells is not well understood. This study investigated whether STARS influenced C2C12 myotube growth by regulating protein synthesis and degradation. The influence of STARS on Pgc-1α, Srf, and Errα mRNA levels, as well as several of their downstream targets involved in muscle cell growth, contraction, and metabolism, was also investigated. STARS overexpression increased actin polymerization, with no effect on protein synthesis, protein degradation, or Akt phosphorylation. STARS overexpression increased Pgc-1α, Srf, Ckmt2, Cpt-1β, and Mhc1 mRNA. STARS knockdown reduced actin polymerization and increased cell death and dead cell protease activity. It also increased markers of inflammation (Casp1, Il-1β, and Mcp-1), regeneration (Socs3 and Myh8), and fast myosin isoforms (Mhc2a and Mhc2x). We show for the first time in muscle cells that STARS overexpression increases actin polymerization and shifts the muscle cell to a more oxidative phenotype. The suppression of STARS causes cell death and increases markers of necrosis, inflammation, and regeneration. As STARS levels are suppressed in clinical models associated with increased necrosis and inflammation, such as aging and limb immobilization, rescuing STARS maybe a future therapeutic strategy to maintain skeletal muscle function and attenuate contraction-induced muscle damage.
骨骼肌质量受感受和传递细胞外机械应激信号至控制蛋白合成和降解的细胞内信号通路的调节。横纹肌 Rho 信号激活蛋白（STARS）是一种肌肉特异性肌动蛋白结合蛋白，对细胞外应激信号敏感。STARS 刺激肌动蛋白聚合，并影响血清反应因子（SRF）和过氧化物酶体增殖物激活受体γ共激活因子（PGC）-1α 转录参与肌肉生长、结构和收缩的基因。STARS 在骨骼肌细胞中的作用尚未完全阐明。本研究通过调节蛋白合成和降解来研究 STARS 是否影响 C2C12 肌管生长。还研究了 STARS 对 Pgc-1α、Srf 和 Errα mRNA 水平及其下游参与肌肉细胞生长、收缩和代谢的几个靶基因的影响。STARS 过表达增加了肌动蛋白聚合，但对蛋白质合成、蛋白质降解或 Akt 磷酸化没有影响。STARS 过表达增加了 Pgc-1α、Srf、Ckmt2、Cpt-1β 和 Mhc1 mRNA。STARS 敲低减少了肌动蛋白聚合并增加了细胞死亡和死细胞蛋白酶活性。它还增加了炎症标志物（Casp1、Il-1β 和 Mcp-1）、再生标志物（Socs3 和 Myh8）和快肌肌球蛋白同工型（Mhc2a 和 Mhc2x）。我们首次在肌肉细胞中表明，STARS 过表达增加了肌动蛋白聚合，并使肌肉细胞向更氧化的表型转变。STARS 的抑制导致细胞死亡并增加坏死、炎症和再生标志物。由于 STARS 水平在与增加的坏死和炎症相关的临床模型中受到抑制，如衰老和肢体固定，因此拯救 STARS 可能是维持骨骼肌功能和减轻收缩引起的肌肉损伤的未来治疗策略。
