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@ARTICLE{GerlachMelhedegaard:643098,
      author       = {Gerlach Melhedegaard, Elise and Rostedt, Fanny and Gineste,
                      Charlotte and Seaborne, Robert A. E. and Dugdale, Hannah F.
                      and Belhac, Vladimir and Zanoteli, Edmar and Lawlor, Michael
                      W. and Mack, David L. and Wallgren-Pettersson, Carina and
                      Hessel, Anthony L. and Jungbluth, Heinz and Laporte, Jocelyn
                      and Saito, Yoshihiko and Nishino, Ichizo and Ochala, Julien
                      and Laitila, Jenni},
      title        = {{M}yosin inhibition partially rescues the myofiber proteome
                      in {X}-linked myotubular myopathy},
      journal      = {JCI insight},
      volume       = {10},
      number       = {24},
      issn         = {2379-3708},
      address      = {Ann Arbor, Michigan},
      publisher    = {JCI Insight},
      reportid     = {PUBDB-2025-05842},
      pages        = {e194868},
      year         = {2025},
      abstract     = {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.},
      cin          = {FS DOOR-User},
      ddc          = {610},
      cid          = {$I:(DE-H253)FS_DOOR-User-20241023$},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3) / FS-Proposal:
                      II-20221421 (II-20221421)},
      pid          = {G:(DE-HGF)POF4-6G3 / G:(DE-H253)II-20221421},
      experiment   = {EXP:(DE-H253)P-P03-20150101},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1172/jci.insight.194868},
      url          = {https://bib-pubdb1.desy.de/record/643098},
}