A therapeutic leap: how myosin inhibitors moved from cardiac interventions to skeletal muscle myopathy solutions
Julius Bogomolovas, Ju Chen
Julius Bogomolovas, Ju Chen
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Commentary

A therapeutic leap: how myosin inhibitors moved from cardiac interventions to skeletal muscle myopathy solutions

Abstract

The myosin inhibitor mavacamten has transformed the management of obstructive hypertrophic cardiomyopathy (HCM) by targeting myosin ATPase activity to mitigate cardiac hypercontractility. This therapeutic mechanism has proven effective for patients with HCM independent of having a primary gene mutation in myosin. In this issue of the JCI, Buvoli et al. report that muscle hypercontractility is a mechanism of pathogenesis underlying muscle dysfunction in Laing distal myopathy, a disorder characterized by mutations altering the rod domain of β myosin heavy chain. The authors performed detailed physiological, molecular, and biomechanical analyses and demonstrated that myosin ATPase inhibition can correct a large extent of muscle abnormalities. The findings offer a therapeutic avenue for Laing distal myopathy and potentially other myopathies. This Commentary underscores the importance of reevaluating myosin activity’s role across myopathies in general for the potential development of targeted myosin inhibitors to treat skeletal muscle disorders.

Authors

Julius Bogomolovas, Ju Chen

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Figure 1

The myosin inhibitor MYK-581 corrects the molecular phenotype of R1500P myofibrils.

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The myosin inhibitor MYK-581 corrects the molecular phenotype of R1500P ...
The equilibrium between the DRX state and the SRX state of βMyHC within the sarcomere favors the SRX state in healthy myofibrils, indicating that more WT βMyHC molecules are present in the SRX state. In contrast, R1500P βMyHC mutations cause the distribution of myosin heads to skew toward the DRX state. While R1500P βMyHC demonstrates near-equal distribution between DRX and SRX states, reflecting the pathological condition of Laing distal myopathy, treatment of R1500P βMyHC myosin–expressing myofibrils with MYK-581 causes a substantial shift toward the SRX state, highlighting the drug’s ability to restore a healthy balance between myosin head states. Notably, the structural effects of the R1500P mutation on the thick filament structure persist despite the shift toward more SRX myosin heads induced by MYK-581 treatment, and the distorted organization of the thick filament caused by the R1500P mutation remains.