<i>Drosophila</i> model of myosin myopathy rescued by overexpression of a TRIM-protein family member.

Abstract

Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in <i>MYH7</i> encoding slow/β-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the α-helical rod domain of <i>MYH7</i> are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative <i>MYH7</i> mutation (K1729del), we have developed a <i>Drosophila melanogaster</i> model of Laing distal myopathy by genomic engineering of the <i>Drosophila Mhc</i> locus. Homozygous <i>Mhc</i>^{<i>K1728del</i>} animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only <i>Mhc</i>^{<i>K1728del</i>} in indirect flight and jump muscles, and heterozygous <i>Mhc</i>^{<i>K1728del</i>} animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of <i>Mhc</i>^{<i>K1728del</i>} mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous <i>Mhc</i>^{<i>K1728del</i>} larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with <i>Mhc</i>^{<i>K1728del</i>} were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in <i>Drosophila</i> recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.