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MYTHO is a novel regulator of skeletal muscle autophagy and integrity

Author

Listed:
  • Jean-Philippe Leduc-Gaudet

    (Research Institute of the McGill University Health Centre
    McGill University Health Centre
    Université du Québec à Montréal
    Veneto Institute of Molecular Medicine)

  • Anais Franco-Romero

    (Veneto Institute of Molecular Medicine
    University of Padova)

  • Marina Cefis

    (Université du Québec à Montréal)

  • Alaa Moamer

    (Research Institute of the McGill University Health Centre)

  • Felipe E. Broering

    (Research Institute of the McGill University Health Centre)

  • Giulia Milan

    (Veneto Institute of Molecular Medicine
    University of Padova)

  • Roberta Sartori

    (Veneto Institute of Molecular Medicine
    University of Padova)

  • Tomer Jordi Chaffer

    (Research Institute of the McGill University Health Centre)

  • Maude Dulac

    (Université du Québec à Montréal)

  • Vincent Marcangeli

    (Université du Québec à Montréal)

  • Dominique Mayaki

    (Research Institute of the McGill University Health Centre)

  • Laurent Huck

    (Research Institute of the McGill University Health Centre)

  • Anwar Shams

    (Taif University)

  • José A. Morais

    (McGill University
    Research Institute of the McGill University Health Center)

  • Elise Duchesne

    (Université du Québec à Chicoutimi)

  • Hanns Lochmuller

    (Children’s Hospital of Eastern Ontario Research Institute
    The Ottawa Hospital
    University of Ottawa)

  • Marco Sandri

    (McGill University Health Centre
    Veneto Institute of Molecular Medicine
    University of Padova)

  • Sabah N. A. Hussain

    (Research Institute of the McGill University Health Centre
    McGill University Health Centre
    Research Institute of the McGill University Health Center)

  • Gilles Gouspillou

    (Research Institute of the McGill University Health Centre
    Université du Québec à Montréal)

Abstract

Autophagy is a critical process in the regulation of muscle mass, function and integrity. The molecular mechanisms regulating autophagy are complex and still partly understood. Here, we identify and characterize a novel FoxO-dependent gene, d230025d16rik which we named Mytho (Macroautophagy and YouTH Optimizer), as a regulator of autophagy and skeletal muscle integrity in vivo. Mytho is significantly up-regulated in various mouse models of skeletal muscle atrophy. Short term depletion of MYTHO in mice attenuates muscle atrophy caused by fasting, denervation, cancer cachexia and sepsis. While MYTHO overexpression is sufficient to trigger muscle atrophy, MYTHO knockdown results in a progressive increase in muscle mass associated with a sustained activation of the mTORC1 signaling pathway. Prolonged MYTHO knockdown is associated with severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and extensive ultrastructural defects, such as accumulation of autophagic vacuoles and tubular aggregates. Inhibition of the mTORC1 signaling pathway in mice using rapamycin treatment attenuates the myopathic phenotype triggered by MYTHO knockdown. Skeletal muscles from human patients diagnosed with myotonic dystrophy type 1 (DM1) display reduced Mytho expression, activation of the mTORC1 signaling pathway and impaired autophagy, raising the possibility that low Mytho expression might contribute to the progression of the disease. We conclude that MYTHO is a key regulator of muscle autophagy and integrity.

Suggested Citation

  • Jean-Philippe Leduc-Gaudet & Anais Franco-Romero & Marina Cefis & Alaa Moamer & Felipe E. Broering & Giulia Milan & Roberta Sartori & Tomer Jordi Chaffer & Maude Dulac & Vincent Marcangeli & Dominique, 2023. "MYTHO is a novel regulator of skeletal muscle autophagy and integrity," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36817-1
    DOI: 10.1038/s41467-023-36817-1
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    References listed on IDEAS

    as
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