title: Modulating myosin restores muscle function in a mouse model of nemaline myopathy.
abstract: 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.
  
  
  CONCLUSIONS
  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. Ann Neurol 2016;79:717-725.
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lindqvist
authors.affiliation: Centre of Human and Aerospace Physiological Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Levy
authors.affiliation: Centre of Human and Aerospace Physiological Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.
authors.forename: Alisha
authors.initials: A
authors.lastname: Pati-Alam
authors.affiliation: Neuromuscular and Regenerative Medicine Unit, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Edna C
authors.initials: EC
authors.lastname: Hardeman
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.|Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia.|Department of Neurology, University of Washington School of Medicine, Seattle, WA.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.affiliation: Centre of Human and Aerospace Physiological Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.
authors.forename: Julien
authors.initials: J
authors.lastname: Ochala