A myopathy-related actin mutation increases contractile function
A myopathy-related actin mutation increases contractile function
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DOI：
10.1007/s00401-012-0962-z
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发表时间：
2012-05-01
影响因子：
12.7
通讯作者：
Ochala, Julien
中科院分区：
文献类型：
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作者：
Lindqvist, Johan;Penisson-Besnier, Isabelle;Ochala, Julien
线状肌病(NM)是最常见的先天性肌病，由多种基因突变引起，包括NEB(NeBulin)、TPM2(β-原肌球蛋白)、TPM3(γ-原肌球蛋白)和ACTA1(骨骼α-肌动蛋白)。20-25%的NM病例携带ACTA1缺陷，这些特殊的突变通常会导致肌动蛋白蛋白中单个残基的替换。尽管临床和科学方面的兴趣与日俱增，但这些微妙的氨基酸替代的收缩后果仍然不清楚。为了解释它们，在本研究中，我们最初记录和分析了肌动蛋白中一种特定的多肽取代的人膜通透性单一肌肉纤维的力学和X射线衍射图，即P.Phe352Ser。结果揭示了一系列意想不到的分子和细胞事件。在收缩过程中，P.Phe352Ser极大地增强了个体交叉桥梁的应变。矛盾的是，P.Phe352Ser还通过改变肌球蛋白头部与肌动蛋白单体的附着率，略微降低了交叉桥的数量。总体而言，在细胞水平上，这些不同的机制有助于改进稳定状态的部队生产。这些结果为未来的治疗策略提供了新的令人惊讶的科学见解和关键信息。
Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure. To decipher them, in the present study, we originally recorded and analysed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibres with a particular peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an unexpected cascade of molecular and cellular events. During contraction, p.Phe352Ser greatly enhances the strain of individual cross-bridges. Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by altering the rate of myosin head attachment to actin monomers. Overall, at the cell level, these divergent mechanisms conduct to an improved steady-state force production. Such results provide new surprising scientific insights and crucial information for future therapeutic strategies.