PDF(Pubmed)
Abstract：
During striated muscle development the first periodically repeated units appear in the premyofibrils, consisting of immature sarcomeres that must undergo a substantial growth both in length and width, to reach their final size. Here we report that, beyond its well established role in sarcomere elongation, the Sarcomere length short (SALS) protein is involved in Z-disc formation and peripheral growth of the sarcomeres. Our protein localization data and loss-of-function studies in the Drosophila indirect flight muscle strongly suggest that radial growth of the sarcomeres is initiated at the Z-disc. As to thin filament elongation, we used a powerful nanoscopy approach to reveal that SALS is subject to a major conformational change during sarcomere development, which might be critical to stop pointed end elongation in the adult muscles. In addition, we demonstrate that the roles of SALS in sarcomere elongation and radial growth are both dependent on formin type of actin assembly factors. Unexpectedly, when SALS is present in excess amounts, it promotes the formation of actin aggregates highly resembling the ones described in nemaline myopathy patients. Collectively, these findings helped to shed light on the complex mechanisms of SALS during the coordinated elongation and thickening of the sarcomeres, and resulted in the discovery of a potential nemaline myopathy model, suitable for the identification of genetic and small molecule inhibitors.
摘要：
在横纹肌发育过程中，第一个周期性重复的单位出现在前肌原纤维中，由未成熟的肉瘤组成，必须在长度和宽度上都经历大量增长，达到最终尺寸。在这里我们报告，除了其在肌节伸长中的公认作用外，肌节长度短（SALS）蛋白参与肌节的Z-盘形成和外周生长。我们在果蝇间接飞行肌肉中的蛋白质定位数据和功能丧失研究强烈表明，肌节的径向生长是在Z盘开始的。至于细丝伸长，我们使用了强大的纳米显微镜方法来揭示SALS在肌节发育过程中会发生重大的构象变化，这对于阻止成人肌肉的尖端伸长可能是至关重要的。此外,我们证明了SALS在肌节伸长和径向生长中的作用都取决于肌动蛋白组装因子的形式。出乎意料的是,当Sals过量存在时，它促进肌动蛋白聚集体的形成，与线虫性肌病患者中描述的非常相似。总的来说，这些发现有助于阐明SALS在肉瘤的协调伸长和增厚过程中的复杂机制，并导致发现了一种潜在的线虫肌病模型，适用于遗传和小分子抑制剂的鉴定。
