Nemaline Myopathy-Related Skeletal Muscle α-Actin (ACTA1) Mutation, Asp286Gly, Prevents Proper Strong Myosin Binding and Triggers Muscle Weakness
Nemaline Myopathy-Related Skeletal Muscle α-Actin (ACTA1) Mutation, Asp286Gly, Prevents Proper Strong Myosin Binding and Triggers Muscle Weakness
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DOI：
10.1371/journal.pone.0045923
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发表时间：
2012-09-20
期刊：
影响因子：
3.7
通讯作者：
Nowak, Kristen J.
中科院分区：
文献类型：
--
作者：
Ochala, Julien;Ravenscroft, Gianina;Nowak, Kristen J.
骨骼肌α-肌动蛋白基因（ACTA 1）的许多突变导致肌无力和线虫性肌病。尽管越来越多的临床和科学的兴趣，虚弱的分子和细胞发病机制仍然不清楚。因此，在本研究中，我们的目的是解开这些机制，从一个转基因小鼠模型表达ACTA 1 Asp 286 Gly突变的线虫性肌病肌肉。我们记录并分析了膜透化的单根肌纤维的力学。我们还进行了分子能态计算的Asp 286 Gly的存在或不存在。结果表明，在收缩过程中，Asp 286 Gly作为一种“毒蛋白”，并根据计算分析，它修改肌动蛋白-肌动蛋白界面。这种现象可能会阻止适当的肌球蛋白交联结合，限制了强结合状态下肌动球蛋白相互作用的分数。在细胞水平上，这会降低力量产生能力，总体而言，会导致肌肉无力。为了平衡这些负面事件，未来潜在的治疗策略可能会集中在不适当的肌动蛋白-肌动蛋白界面或肌球蛋白结合。
Many mutations in the skeletal muscle alpha-actin gene (ACTA1) lead to muscle weakness and nemaline myopathy. Despite increasing clinical and scientific interest, the molecular and cellular pathogenesis of weakness remains unclear. Therefore, in the present study, we aimed at unraveling these mechanisms using muscles from a transgenic mouse model of nemaline myopathy expressing the ACTA1 Asp286Gly mutation. We recorded and analyzed the mechanics of membranepermeabilized single muscle fibers. We also performed molecular energy state computations in the presence or absence of Asp286Gly. Results demonstrated that during contraction, the Asp286Gly acts as a "poison-protein'' and according to the computational analysis it modifies the actin-actin interface. This phenomenon is likely to prevent proper myosin crossbridge binding, limiting the fraction of actomyosin interactions in the strong binding state. At the cell level, this decreases the force-generating capacity, and, overall, induces muscle weakness. To counterbalance such negative events, future potential therapeutic strategies may focus on the inappropriate actin-actin interface or myosin binding.