Modulating myosin restores muscle function in a mouse model of nemaline myopathy

OBJECTIVE: Nemaline myopathy, one of the most common congenital myopathies is associated with mutations in various genes including ACTA1. This disease is also characterised 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 fibres. ACTA1 mutations are also associated with variations in myofibre 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 (i) would directly be due to the inefficient actomyosin complex, and (ii) could be restored by manipulating myosin expression. METHODS: We used a knock-in 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 harbouring a myosin transgene known to facilitate muscle contraction. RESULTS: We observed that in presence of the transgene, the intrinsic force-generating capacity was restored and myofibre size was normal. INTERPRETATION: This demonstrates a direct link between disrupted attachment of myosin molecules to actin monomers and muscle fibre atrophy. These data also suggest that further therapeutic interventions should primarily target myosin dysfunction to alleviate the pathology of ACTA1-related nemaline myopathy.