Abstract
ObjectiveNemaline 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.MethodsWe 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.ResultsWe observed that in the presence of the transgene, the intrinsic force‐generating capacity was restored and myofiber size was normal.InterpretationThis 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
Highlights
ObjectiveOne of the most common congenital myopathies, is associated with mutations in various genes including ACTA1
Myofiber Atrophy Appeared at 8 Weeks of Age in Transgenic Mice To determine whether muscle cells were atrophic or hypotrophic as a consequence of ACTA1 mutation, we evaluated the cross-sectional area (CSA) of fibers at different age points in transgenic mice (2 days, 14 days, 4 weeks, 8 weeks, and 12 weeks after birth)
MYL4 as a Potential Future Therapy for Nemaline Myopathy Interestingly, the results of the present study demonstrate that a molecular intervention designed to promote expression of MyLC1a/emb in skeletal musculature can ameliorate features of pathology associated with ACTA1related nemaline myopathy
Summary
One of the most common congenital myopathies, is associated with mutations in various genes including ACTA1. MyLC1a/emb, which is encoded by the MYL4 gene and only present in the heart and skeletal muscles of embryos, increases the force-generating capacity of myosin molecules.[11] From that, we hypothesized that inducing expression of MyLC1a/emb in mature skeletal myofibers via transgene delivery (with recombinant adeno-associated virus [rAAV] vectors containing the MYL4 gene) would (1) improve the interactions between myosin and actin filaments in wild-type mice, (2) restore the contractile function in the knockin transgenic mouse model, and (3) prevent atrophy or hypotrophy by ameliorating the mechanosensitive pathways responsible for protein turnover. Our findings suggest that MYL4-directed interventions could offer promising therapeutic potential for the treatment of neuromuscular disorders where an impaired myosin binding is observed
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