MYTHO is a novel regulator of skeletal muscle autophagy and integrity


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Leduc-Gaudet, J. P., Franco-Romero, A., Cefis, M., Moamer, A., Broering, F. E., Milan, G., Sartori, R., Chaffer, T. J., Dulac, M., Marcangeli, V., Mayaki, D., Huck, L., Shams, A., Morais, J. A., Duchesne, E., Lochmuller, H., Sandri, M., Hussain, S. N. A. et Gouspillou, G. (2023). MYTHO is a novel regulator of skeletal muscle autophagy and integrity. Nature Communications, 14 (1). Article 1199. ISSN 2041-1723 DOI 10.1038/s41467-023-36817-1

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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.

Type de document: Article
Mots-clés libres: Bioaccumulation Cancer Muscle Phenotype Signaling Mammalian target of rapamycin complex 1 Adolescent Animal Autophagy Genetics Human Macroautophagy Mouse Muscle atrophy Myotonic dystrophy Skeletal muscle Animals Humans Mechanistic Target of Rapamycin Complex 1 Mice Muscle, Skeletal Muscular Atrophy
Date de dépôt: 10 juill. 2023 18:25
Dernière modification: 10 juill. 2023 18:25
Version du document déposé: Version officielle de l'éditeur

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