2025/11/04 by Elise G. Melhedegaard, F. Rostedt, Charlotte Gineste +14 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Cardiomyopathy and Myosin Studies #Cellular transport and secretion #Muscle Physiology and Disorders
paper · pdf · doi:10.1172/jci.insight.194868
openalex publication_date 2025/11/04 · openalex created_date 2025/11/04 · openalex updated_date 2026/07/22
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.