Modulating myosin restores muscle function in a mouse model of nemaline myopathy.
Modulating myosin restores muscle function in a mouse model of nemaline myopathy.
复制标题
DOI：
10.1002/ana.24619
复制
发表时间：
2016-05
影响因子：
11.2
通讯作者：
Ochala J
中科院分区：
文献类型：
--
作者：
Lindqvist J;Levy Y;Pati-Alam A;Hardeman EC;Gregorevic P;Ochala J
线状肌病是最常见的先天性肌病之一，与包括ACTA1在内的多种基因突变有关。这种疾病的另一个特点是各种形式/程度的肌肉无力，大多数病例很严重，导致婴儿死亡。最近的发现为潜在的病理生理机制提供了有价值的见解。ACTA1的突变直接破坏了肌动蛋白和肌球蛋白之间的结合相互作用，从而破坏了肌纤维的内在发力能力。ACTA1突变也与肌纤维大小的变化有关，其机制尚不清楚。在本研究中，我们试图验证以下假设，即携带ACTA1突变的骨骼肌的功能和形态属性受损(1)将直接归因于肌动球蛋白复合物的低效，(2)可以通过操纵肌动蛋白表达来恢复。我们使用敲入小鼠模型表达在人类患者中发现的ACTA1 His40Tyr肌动蛋白突变。然后，我们进行了体内肌内注射重组腺相关病毒载体，其中含有一种已知可促进肌肉收缩的肌球蛋白转基因基因。我们观察到，在转基因的存在下，内力产生能力恢复，肌纤维大小正常。这表明肌凝蛋白分子与肌动蛋白单体的连接中断与肌纤维萎缩之间存在直接联系。这些数据还表明，进一步的治疗干预应主要针对肌球蛋白功能障碍，以减轻ACTA1相关的线状肌病的病理。Ann Neurol 2016；79:717 - 725
Nemaline myopathy, one of the most common congenital myopathies, is associated with mutations in various genes including ACTA1. This disease is also characterized by various forms/degrees of muscle weakness, with most cases being severe and resulting in death in infancy. Recent findings have provided valuable insight into the underlying pathophysiological mechanisms. Mutations in ACTA1 directly disrupt binding interactions between actin and myosin, and consequently the intrinsic force‐generating capacity of muscle fibers. ACTA1 mutations are also associated with variations in myofiber size, the mechanisms of which have been unclear. In the present study, we sought to test the hypotheses that the compromised functional and morphological attributes of skeletal muscles bearing ACTA1 mutations (1) would be directly due to the inefficient actomyosin complex and (2) could be restored by manipulating myosin expression. We used a knockin mouse model expressing the ACTA1 His40Tyr actin mutation found in human patients. We then performed in vivo intramuscular injections of recombinant adeno‐associated viral vectors harboring a myosin transgene known to facilitate muscle contraction. We observed that in the presence of the transgene, the intrinsic force‐generating capacity was restored and myofiber size was normal. This demonstrates a direct link between disrupted attachment of myosin molecules to actin monomers and muscle fiber atrophy. These data also suggest that further therapeutic interventions should primarily target myosin dysfunction to alleviate the pathology of ACTA1‐related nemaline myopathy. Ann Neurol 2016;79:717–725