Myosin storage myopathy mutations cause age dependent muscle degeneration and cardiac dysfunction in a Drosophila model. Meera Cozhimuttam Viswanathan^1,2, William Kronert¹, Girish Melkani¹, Anthony Cammarato², Sanford Bernstein¹. 1) Department of Molecular Biology and SDSU heart institute. San Diego State Univ, San Diego, CA; 2) Johns Hopkins School of Medicine, Baltimore, MD.

   Myosin storage myopathy (MSM) is a rare congenital disorder caused by mutations in the -cardiac MHC rod and characterized by subsarcolemmal accumulation of -cardiac myosin that has a hyaline appearance. These mutations map near to or within the assembly competence domain that is crucial to filament assembly. We hypothesize that mutations change hydropathy or charge of residues in the heptad repeat thus altering interactions necessary for assembly of coiled-coil rod dimers or thick filaments causing aggregation. We have made a Drosophila model for MSM for pursuing mechanistic investigations, which makes it possible to examine interactions between wild-type and mutant full-length myosins, as the majority of mutant alleles are dominant. We introduced the R1845W, L1793P or the E1883K mutation into Drosophila MHC transgene and expressed each in the jump/ indirect flight muscles (IFM). Our studies show a severe reduction in the flight and jump ability of both homozygous and heterozygous transgenic flies with an age-dependent loss of muscle function. Electron and confocal microscopy of the IFM of transgenic lines show myofibrillar disarray with large areas of granular/ filamentous inclusions similar to hyaline bodies found in affected humans. In addition, heterozygotes of at least two mutants show restrictive cardiomyopathy phenotypes with arrhythmia that mirrors cardiomyopathy reported in human subjects. Life spans of the MSM mutants are also reduced compared to transgenic control. We plan to study in vitro filament forming ability of the mutant myosin to determine if defective filament formation or instability of the myosin filaments is the basis of MSM. Our study will be an important step in exploring the mechanistic basis of MSM, and identify potential therapeutic approaches by over-expressing myosin chaperones or autophagic response.