MYTHO is a novel regulator of skeletal muscle autophagy and integrity

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 Mayaki, Laurent Huck, Anwar Shams, José A. Morais, Elise Duchesne, Hanns Lochmuller, Marco Sandri (), Sabah N. A. Hussain () and Gilles Gouspillou ()
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Jean-Philippe Leduc-Gaudet: Research Institute of the McGill University Health Centre
Anais Franco-Romero: Veneto Institute of Molecular Medicine
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
Roberta Sartori: Veneto Institute of Molecular Medicine
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
Elise Duchesne: Université du Québec à Chicoutimi
Hanns Lochmuller: Children’s Hospital of Eastern Ontario Research Institute
Marco Sandri: McGill University Health Centre
Sabah N. A. Hussain: Research Institute of the McGill University Health Centre
Gilles Gouspillou: Research Institute of the McGill University Health Centre

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36817-1

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