Myosin inhibition partially rescues the myofibre proteome in X-linked myotubular myopathy

Elise Gerlach Melhedegaard; Fanny Rostedt; Charlotte Gineste; Robert A.E. Seaborne; Hannah F. Dugdale; Vladimir Belhac; Edmar Zanoteli; Michael W. Lawlor; David L. Mack; Carina Wallgren-Pettersson; Anthony L. Hessel; Heinz Jungbluth; Jocelyn Laporte; Yoshihiko Saito; Ichizo Nishino; Julien Ochala; Jenni Laitila

doi:10.1172/jci.insight.194868

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

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¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

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¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

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¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

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¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

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¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Belhac, V. in: PubMed | Google Scholar

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Zanoteli, E. in: PubMed | Google Scholar

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Lawlor, M. in: PubMed | Google Scholar

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Mack, D. in: PubMed | Google Scholar

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Wallgren-Pettersson, C. in: PubMed | Google Scholar

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Hessel, A. in: PubMed | Google Scholar |

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Jungbluth, H. in: PubMed | Google Scholar

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Laporte, J. in: PubMed | Google Scholar |

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Saito, Y. in: PubMed | Google Scholar

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Nishino, I. in: PubMed | Google Scholar |

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Ochala, J. in: PubMed | Google Scholar

¹Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

²IGBMC, CNRS UMR 7104, Inserm U 1258, Strasbourg University, Illkirch, France

³School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom

⁴Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

⁵Department of Pathology and Laboratory Medicine, Diverge Translational Science Laboratory and Medical College of Wisconsin, Milwaukee, United States of America

⁶Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States of America

⁷Folkhälsan Research Center, Helsinki, Finland

⁸Institute of Physiology II, University of Muenster, Muenster, Germany

⁹Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom

¹⁰Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

Find articles by Laitila, J. in: PubMed | Google Scholar

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 human patients and canine/mouse models; we performed Mant-ATP chase experiments coupled with X-ray diffraction analyses and LC/MS-based proteomics studies. In XLMTM humans, 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 remodelling of the myofibre 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 four-week treatment period, we observed a partial restoration of the myofibre proteome, especially proteins involved in cytoskeletal, sarcomeric and energetic pathways. Altogether, our study highlights myosin inhibition as a new potential drug mechanism for the complex XLMTM muscle phenotype.

Myosin inhibition partially rescues the myofibre proteome in X-linked myotubular myopathy

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Myosin inhibition partially rescues the myofibre proteome in X-linked myotubular myopathy

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