肌球蛋白
MYH7
骨骼肌
肌病
突变
生物
心肌细胞
运动性
肌球蛋白轻链激酶
细胞生物学
表型
肌动蛋白
肌球蛋白ATP酶
ATP酶
生物化学
基因
遗传学
酶
解剖
作者
Alexander K. Sonne,Lorenzo Peverelli,Aurelio Hernández-Laín,Cristina Ruesca Domínguez,Jesper L. Andersen,Margherita Milone,Alan H. Beggs,Julien Ochala
出处
期刊:American Journal of Physiology-cell Physiology
[American Physiological Society]
日期:2023-03-01
卷期号:324 (3): C769-C776
被引量:3
标识
DOI:10.1152/ajpcell.00002.2023
摘要
Congenital myopathies are a vast group of genetic muscle diseases. Among the causes are mutations in the MYH2 gene resulting in truncated type IIa myosin heavy chains (MyHCs). The precise cellular and molecular mechanisms by which these mutations induce skeletal muscle symptoms remain obscure. Hence, in the present study, we aimed to explore whether such genetic defects would alter the presence as well as the post-translational modifications of MyHCs and the functionality of myosin molecules. For this, we dissected muscle fibers from four myopathic patients with MYH2 truncating mutations and from five human healthy controls. We then assessed 1) MyHCs presence/post-translational modifications using LC/MS; 2) relaxed myosin conformation and concomitant ATP consumption with a loaded Mant-ATP chase setup; 3) myosin activation with an unloaded in vitro motility assay; and 4) cellular force production with a myofiber mechanical setup. Interestingly, the type IIa MyHC with one additional acetylated lysine (Lys35-Ac) was present in the patients. This was accompanied by 1) a higher ATP demand of myosin heads in the disordered-relaxed conformation; 2) faster actomyosin kinetics; and 3) reduced muscle fiber force. Overall, our findings indicate that MYH2 truncating mutations impact myosin presence/functionality in human adult mature myofibers by disrupting the ATPase activity and actomyosin complex. These are likely important molecular pathological disturbances leading to the myopathic phenotype in patients.
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