model of myosin myopathy rescued by overexpression of a TRIM-protein family member.

Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in 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 are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative mutation (K1729del), we have developed a model of Laing distal myopathy by genomic engineering of the locus. Homozygous animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only in indirect flight and jump muscles, and heterozygous animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous 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 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 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.