Myosin inhibition partially rescues the myofiber proteome in X-linked myotubular myopathy
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.
Authors
- Charlotte Gineste (ORCID: https://orcid.org/0000-0001-8515-089X)
- Robert A. Seaborne (ORCID: https://orcid.org/0000-0003-2491-3747)
- Hannah F. Dugdale (ORCID: https://orcid.org/0000-0003-2571-0968)
- David L. Mack (ORCID: https://orcid.org/0000-0003-1340-7056)
- Julien Ochala (ORCID: https://orcid.org/0000-0002-6358-2920)
- Michael W. Lawlor (ORCID: https://orcid.org/0000-0003-0731-3950)
- Heinz Jungbluth (ORCID: https://orcid.org/0000-0002-7159-3427)
- Anthony L. Hessel (ORCID: https://orcid.org/0000-0003-4278-4221)
- Edmar Zanoteli (ORCID: https://orcid.org/0000-0002-4991-6760)
- Jenni Laitila (ORCID: https://orcid.org/0000-0002-0076-3038)
- Yoshihiko Saito (ORCID: https://orcid.org/0000-0001-5574-3571)
- Ichizo Nishino (ORCID: https://orcid.org/0000-0001-9452-112X)
- Jocelyn Laporte (ORCID: https://orcid.org/0000-0001-8256-5862)
- Elise Gerlach Melhedegaard (ORCID: https://orcid.org/0000-0002-8605-7707)
- Carina Wallgren-Pettersson
- F. Rostedt
- Vladimir Belhac
Institutions
- University of Copenhagen (DK)
- Centre National de la Recherche Scientifique (FR)
- University of Helsinki (FI)
- Loughborough University (GB)
- Inserm (FR)
- Universidade de São Paulo (BR)
- King's College London (GB)
- California Institute for Regenerative Medicine (US)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- University of Washington (US)
- Medical College of Wisconsin (US)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- National Center of Neurology and Psychiatry (JP)
- Department of Physiological Sciences (RU)
- Bioengineering Center (RU)
- Folkhälsans Forskningscentrum (FI)
- Université de Strasbourg (FR)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-11-04
- DOI
- https://doi.org/10.1172/jci.insight.194868
- Citations
- 1
- Primary Topic
- Cardiomyopathy and Myosin Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.39
Funders
- Finska Läkaresällskapet
- Lundbeckfonden
- Jane ja Aatos Erkon Säätiö
- Novo Nordisk
- Copenhagen Graduate School for Nanoscience and Nanotechnology
- Novo Nordisk Fonden
- National Institutes of Health
- Deutsches Elektronen-Synchrotron