In a mouse model of X-linked myotubular myopathy, a 4-week treatment with the myosin ATPase inhibitor mavacamten partially restored the dysregulated sarcomeric and energetic myofiber proteome.
Does mavacamten improve the myofiber proteome in mice lacking MTM1?
Myosin inhibition with mavacamten partially restores the myofiber proteome in a mouse model of X-linked myotubular myopathy, highlighting a potential new therapeutic mechanism.
X-linked myotubular myopathy (XLMTM) due to MTM1 mutations is a rare and often lethal congenital myopathy. Its downstream molecular and cellular mechanisms are currently incompletely understood. The most abundant protein in muscle, myosin, has been implicated in the pathophysiology of other congenital myopathies. Hence, in the present study, we aimed to define whether myosin is also dysfunctional in XLMTM and whether it, thus, may constitute a potential drug target. To this end, we used skeletal muscle tissue from patients and canine/mouse models; we performed Mant-ATP chase experiments coupled with x-ray diffraction analyses and LC/MS-based proteomics studies. In patients with XLMTM, we found that myosin molecules are structurally disordered and preferably adopt their ATP-consuming biochemical state. This phosphorylation-related (mal)adaptation was mirrored by a striking remodeling of the myofiber energetic proteome in XLMTM dogs. In line with these, we confirmed an accrued myosin ATP consumption in mice lacking MTM1. Hence, we treated these with a myosin ATPase inhibitor, mavacamten. After a 4-week treatment period, we observed a partial restoration of the myofiber proteome, especially proteins involved in cytoskeletal, sarcomeric, and energetic pathways. Altogether, our study highlights myosin inhibition as a potentially new drug mechanism for the complex XLMTM muscle phenotype.
Melhedegaard et al. (Tue,) conducted a other in X-linked myotubular myopathy (n=13). Mavacamten vs. Vehicle/Placebo was evaluated on Myofiber proteome restoration and myosin ATP consumption. In a mouse model of X-linked myotubular myopathy, a 4-week treatment with the myosin ATPase inhibitor mavacamten partially restored the dysregulated sarcomeric and energetic myofiber proteome.