Key result
Myosin storage myopathy mutations cut thick filament length ~40% and impair muscle function in Drosophila.
Why the study?
Myosin storage myopathy is caused by mutations in the slow muscle/β-cardiac MHC gene that frequently disrupt the stabilizing heptad repeat motif, but their dominant physiological and structural effects required examination.
Absolute Event Rate: 1.48% vs 2.45%
p-value: p=<0.0001
Drosophila models of myosin storage myopathy mutations demonstrate that these variants act dominantly to disrupt thick filament structure, leading to skeletal muscle dysfunction and restrictive cardiomyopathy.
Drosophila model supports dominant myosin mutations in myopathy; leaves open mammalian validation and human therapeutic translation.
Myosin storage myopathy (MSM) is a rare skeletal muscle disorder caused by mutations in the slow muscle/β-cardiac myosin heavy chain (MHC) gene. MSM missense mutations frequently disrupt the tail's stabilizing heptad repeat motif. Disease hallmarks include subsarcolemmal hyaline-like β-MHC aggregates, muscle weakness, and, occasionally, cardiomyopathy. We generated transgenic, heterozygous Drosophila to examine the dominant physiological and structural effects of the L1793P, R1845W, and E1883K MHC MSM mutations on diverse muscles. The MHC variants reduced lifespan and flight and jump abilities. Moreover, confocal and electron microscopy revealed that they provoked indirect flight muscle breaks and myofibrillar disarray/degeneration with filamentous inclusions. Incorporation of GFP-myosin enabled in situ determination of thick filament lengths, which were significantly reduced in all mutants. Semiautomated heartbeat analysis uncovered aberrant cardiac function, which worsened with age. Thus, our fly models phenocopied traits observed among MSM patients. We additionally mapped the mutations onto a recently determined, 6 Å resolution, cryo-EM structure of the human cardiac thick filament. The R1845W mutation replaces a basic arginine with a polar-neutral, bulkier tryptophan, while E1883K reverses charge at critical filament loci. Both would be expected to disrupt the core and the outer shell of the backbone structure. Replacing L1793 with a proline, a potent breaker of α-helices, could disturb the coiled-coil of the myosin rod and alter the tail-tail interactome. Hence, all mutations likely destabilize and weaken the filament backbone. This may trigger disease in humans, while potentially analogous perturbations are likely to yield the observed thick filament and muscle disruption in our fly models.
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Viswanathan et al. (2024) studied Myosin storage myopathy. Heterozygous MSM mutations (L1793P, R1845W, E1883K) vs. Transgenic wildtype (PwMhc2) was evaluated on Thick filament length (µm) (p=<0.0001). Heterozygous expression of myosin storage myopathy mutations in Drosophila significantly reduced thick filament length (1.48-1.61 µm vs 2.45 µm) and impaired muscle function and lifespan.
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