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Nemaline Myopathy-Related Skeletal Muscle alpha-Actin (ACTA1) Mutation, Asp286Gly, Prevents Proper Strong Myosin Binding and Triggers Muscle Weakness
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, e45923- p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2012. Vol. 7, no 9, e45923- p.
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-184466DOI: 10.1371/journal.pone.0045923ISI: 000309388900112OAI: oai:DiVA.org:uu-184466DiVA: diva2:566626
Available from: 2012-11-09 Created: 2012-11-07 Last updated: 2017-12-07Bibliographically approved

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