King's College London

Research portal

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

Research output: Contribution to journalArticlepeer-review

Johan Lindqvist, Yotam Levy, Alisha Pati-Alam, Edna C. Hardeman, Paul Gregorevic, Julien Ochala

Original languageEnglish
Pages (from-to)717–725
JournalAnnals of Neurology
Issue number5
Early online date22 Mar 2016
Accepted/In press16 Feb 2016
E-pub ahead of print22 Mar 2016
PublishedMay 2016


King's Authors



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.


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.


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


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. 

Download statistics

No data available

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454