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Modulating Myosin Restores Muscle Function in a Mouse Model of Nemaline Myopathy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Kings Coll London, Fac Life Sci & Med, Ctr Human & Aerosp Physiol Sci, Guys Campus,Shepherds House,Room 3-3, London SE1 1UL, England..
Kings Coll London, Fac Life Sci & Med, Ctr Human & Aerosp Physiol Sci, Guys Campus,Shepherds House,Room 3-3, London SE1 1UL, England..
Univ New S Wales, Sch Med Sci, Neuromuscular & Regenerat Med Unit, Sydney, NSW, Australia..
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2016 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 79, no 5, 717-725 p.Article in journal (Refereed) PublishedText
Abstract [en]

Objective: Nemaline myopathy, one of the most common congenital myopathies, is associated with mutations in various genes including ACTA1. This disease is also characterized by various forms/degrees of muscle weakness, with most cases being severe and resulting in death in infancy. Recent findings have provided valuable insight into the underlying pathophysiological mechanisms. Mutations in ACTA1 directly disrupt binding interactions between actin and myosin, and consequently the intrinsic force-generating capacity of muscle fibers. ACTA1 mutations are also associated with variations in myofiber size, the mechanisms of which have been unclear. In the present study, we sought to test the hypotheses that the compromised functional and morphological attributes of skeletal muscles bearing ACTA1 mutations (1) would be directly due to the inefficient actomyosin complex and (2) could be restored by manipulating myosin expression.

Methods: We used a knockin mouse model expressing the ACTA1 His40Tyr actin mutation found in human patients. We then performed in vivo intramuscular injections of recombinant adeno-associated viral vectors harboring a myosin transgene known to facilitate muscle contraction.

Results: We observed that in the presence of the transgene, the intrinsic force-generating capacity was restored and myofiber size was normal.

Interpretation: This demonstrates a direct link between disrupted attachment of myosin molecules to actin monomers and muscle fiber atrophy. These data also suggest that further therapeutic interventions should primarily target myosin dysfunction to alleviate the pathology of ACTA1-related nemaline myopathy.

Place, publisher, year, edition, pages
2016. Vol. 79, no 5, 717-725 p.
National Category
URN: urn:nbn:se:uu:diva-297279DOI: 10.1002/ana.24619ISI: 000375752100003OAI: diva2:941862
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2016-06-23 Created: 2016-06-22 Last updated: 2016-06-23Bibliographically approved

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