Nemaline Myopathy-Related Skeletal Muscle α-Actin ACTA1 Mutation, Asp286Gly, Prevents Proper Strong Myosin Binding and Triggers Muscle WeaknessReportar como inadecuado




Nemaline Myopathy-Related Skeletal Muscle α-Actin ACTA1 Mutation, Asp286Gly, Prevents Proper Strong Myosin Binding and Triggers Muscle Weakness - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Many mutations in the skeletal muscle α-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 membrane-permeabilized 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 cross-bridge 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.



Autor: Julien Ochala , Gianina Ravenscroft, Nigel G. Laing, Kristen J. Nowak

Fuente: http://plos.srce.hr/



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