Cavin4b/Murcb Is Required for Skeletal Muscle Development and Function in Zebrafish

Skeletal muscles provide metazoans with the ability to feed, reproduce and avoid predators. In humans, a heterogeneous group of genetic diseases, termed muscular dystrophies (MD), lead to skeletal muscle dysfunction. Mutations in the gene encoding Caveolin-3, a principal component of the membrane micro-domains known as caveolae, cause defects in muscle maintenance and function; however it remains unclear how caveolae dysfunction underlies MD pathology. The Cavin family of caveolar proteins can form membrane remodeling oligomers and thus may also impact skeletal muscle function. Changes in the distribution and function of Cavin4/Murc, which is predominantly expressed in striated muscles, have been reported to alter caveolae structure through interaction with Caveolin-3. Here, we report the generation and phenotypic analysis of murcb mutant zebrafish, which display impaired swimming capacity, skeletal muscle fibrosis and T-tubule abnormalities during development. To understand the mechanistic importance of Murc loss of function, we assessed Caveolin-1 and 3 localization and found it to be abnormal. We further identified an in vivo function for Murc in Erk signaling. These data link Murc with developmental defects in T-tubule formation and progressive muscle dysfunction, thereby providing a new candidate for the etiology of muscular dystrophy.骨骼肌赋予后生动物（metazoans）摄食、繁殖以及躲避天敌的能力。在人类中，一类异质性遗传疾病——肌营养不良症（muscular dystrophies, MD）——会引发骨骼肌功能障碍。编码小窝蛋白-3（Caveolin-3）的基因发生突变，该蛋白是被称为小窝（caveolae）的膜微结构域的核心组分，会导致肌肉维持与功能出现缺陷；然而目前仍不清楚小窝功能异常如何介导肌营养不良症的病理进程。Cavin家族小窝蛋白可形成膜重塑型寡聚体，故而同样可能对骨骼肌功能产生影响。研究表明，主要在横纹肌中表达的Cavin4/Murc，其分布与功能改变可通过与小窝蛋白-3相互作用来改变小窝结构。本研究报道了murcb基因突变斑马鱼的构建及其表型分析结果，该突变体在发育过程中表现出游泳能力受损、骨骼肌纤维化以及横小管（T-tubule）异常等表型。为阐明Murc功能缺失的分子机制，我们检测了小窝蛋白-1（Caveolin-1）与小窝蛋白-3的定位情况，发现其定位出现异常。我们还进一步证实了Murc在细胞外调节蛋白激酶（Extracellular signal-regulated kinase, Erk）信号通路中的体内功能。上述研究结果将Murc与横小管形成的发育缺陷以及进行性肌肉功能障碍联系起来，从而为肌营养不良症的病因学研究提供了新的候选靶点。