School of Biological Sciences, Monash University, Melbourne 3800, Australia.
Hum Mol Genet. 2012 Sep 15;21(18):4073-83. doi: 10.1093/hmg/dds231. Epub 2012 Jun 16.
Myofibrillar myopathies are a group of muscle disorders characterized by the disintegration of skeletal muscle fibers and formation of sarcomeric protein aggregates. All the proteins known to be involved in myofibrillar myopathies localize to a region of the sarcomere known as the Z-disk, the site at which defects are first observed. Given the common cellular phenotype observed in this group of disorders, it is thought that there is a common mechanism of pathology. Mutations in filamin C, which has several proposed roles in the development and function of skeletal muscle, can result in filamin-related myofibrillar myopathy. The lack of a suitable animal model system has limited investigation into the mechanism of pathology in this disease and the role of filamin C in muscle development. Here, we characterize stretched out (sot), a zebrafish filamin Cb mutant, together with targeted knockdown of zebrafish filamin Ca, revealing fiber dissolution and formation of protein aggregates strikingly similar to those seen in filamin-related myofibrillar myopathies. Through knockdown of both zebrafish filamin C homologues, we demonstrate that filamin C is not required for fiber specification and that fiber damage is a consequence of muscle activity. The remarkable similarities in the myopathology between our models and filamin-related myofibrillar myopathy makes them suitable for the study of these diseases and provides unique opportunities for the investigation of the function of filamin C in muscle and development of therapies.
肌原纤维肌病是一组肌肉疾病，其特征是骨骼肌纤维崩解和肌节蛋白聚集体的形成。所有已知与肌原纤维肌病有关的蛋白都定位于肌节的一个区域，即 Z 盘，这是首先观察到缺陷的部位。鉴于该组疾病中观察到的共同细胞表型，人们认为存在共同的病理学机制。细丝蛋白 C 的突变，其在骨骼肌的发育和功能中有几个被提议的作用，可导致与细丝蛋白相关的肌原纤维肌病。缺乏合适的动物模型系统限制了对该疾病病理学机制和细丝蛋白 C 在肌肉发育中的作用的研究。在这里，我们描述了拉长（sot），一种斑马鱼细丝蛋白 Cb 突变体，以及靶向敲低斑马鱼细丝蛋白 Ca，显示纤维溶解和蛋白聚集体的形成与细丝蛋白相关的肌原纤维肌病非常相似。通过敲低两种斑马鱼细丝蛋白 C 同源物，我们证明细丝蛋白 C 不是纤维特化所必需的，并且纤维损伤是肌肉活动的结果。我们的模型与细丝蛋白相关的肌原纤维肌病之间在肌病学上的惊人相似之处使它们适合于这些疾病的研究，并为细丝蛋白 C 在肌肉和治疗方法的发展中的功能研究提供了独特的机会。
