Mechanism of heart failure in cardiomyopathy based on cytoskeletal abnormality

在人类和动物模型中，由肌营养不良蛋白或肌聚糖的遗传缺陷引起的肌营养不良蛋白-糖蛋白复合物（DGC）的破坏可导致肌肉营养不良和/或心肌病。然而，导致肌细胞退化的关键早期分子事件仍然难以捉摸。我们在最近的研究中表明，拉伸敏感的阳离子选择通道是活跃的，Ca^<2+>进入在心肌病仓鼠制备的静息培养肌管中增强（BIO14.6）。为了确定Ca^<2+>的进入机制可能与肌细胞变性的发病机制有关，我们在横纹肌中寻找并克隆了一个生长因子调节通道（GRC）。GRC是一种Ca~<2+> -可渗透的非选择性阳离子通道，属于瞬时受体电位（TRP）通道家族，它响应生长因子如IGF-I和FCS从细胞内部转运到细胞表面。δ-肌聚糖的肌膜中GRC升高。然而，总细胞GRC在正常和营养不良肌肉之间没有显著差异。对δ-肌聚糖缺乏的BIO 14.6仓鼠制备的肌管的特性分析表明，GRC在肌细胞拉伸的反应中被激活，并负责增强Ca^<2+>内流和由此产生的细胞损伤（通过肌酸磷酸激酶外流测量）。我们发现细胞拉伸增加了GRC向肌膜的转运，这需要外部Ca^<2+>的进入。

Disruption of the dystrophin-glycoprotein complex (DGC) caused by genetic defects of dystrophin or sarcoglycans results in muscular dystrophy and/or cardiomyopathy in humans and animal models. However, the key early molecular events leading to myocyte degeneration remain elusive. We have shown in recent work that stretch-sensitive cation-selective channels are active and Ca^<2+> entry is enhanced in resting cultured myotubes prepared from cardiomyopathic hamster (BIO14.6). To identify Ca^<2+> entry mechanisms possibly responsible for the pathogenesis of myocyte degeneration we searched for and cloned a growth factor-regulated channel (GRC) in striated muscle. GRC is a Ca~<2+> -permeable nonselective cation channel belonging to the transient-receptor-potential (TRP) channel family, which translocates from the cell interior to the surface in response to growth factors such as IGF-I and FCS. GRC is elevated in the sarcolemma of δ-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from δ-sarcoglycan-deficient BIO 14.6 hamsters revealed that GRC is activated in response to myocyte stretch and is responsible for enhanced Ca^<2+> influx and resultant cell damage as measured by creatine phosphokinase efflux. We found that cell stretch increased GRC translocation to the sarcolemma, which requires entry of external Ca^<2+>.