MYTHO: A novel regulator of autophagy and skeletal muscle health

Jean-Philippe Leduc-Gaudet, Anaïs Franco-Romero, Felipe E. Broering, Alaa Moamer, Marina Cefis, Tomer J. Chaffer, Maude Dulac, Vincent Marcangeli, Sami Sedraoui, Anwar Shams, Dominique Mayaki, Laurent Huck, Basil Petrof, Hanns Lochmuller, Marco Sandri, Sabah N. Hussain, Gilles Gouspillou

Research output: Contribution to journalArticleAcademicpeer-review


RATIONALE: The loss of skeletal muscle function can have dramatic health consequence. Skeletal muscle dysfunction are found in a wide range of clinical conditions, including cancer cachexia, starvation, sepsis, and aging. Autophagy is an essential catabolic process that remove damaged cytosolic components. Accumulating evidence indicates that insufficient or excessive autophagy can contribute to the development of skeletal muscle atrophy. We recently identified a novel FoxO-dependent gene, which we named MYTHO, with the potential to regulate autophagy in skeletal muscles. However, to date, the roles that MYTHO plays in skeletal muscles remain unknown. In this study, we evaluated the functional importance of MYTHO in skeletal muscle structure and function. METHODS: To study the functional importance of MYTHO in skeletal muscle mass and function, we used a combination of genetic strategies in mice to delete or overexpress MYTHO. RESULTS: MYTHO expression is induced in various muscle wasting conditions, including starvation, denervation, cancer cachexia, and sepsis. Using different genetics approaches, we confirmed that MYTHO is an important regulator of autophagy in skeletal muscle. Importantly, we also found that MYTHO knockdown in skeletal muscles caused various myopathic features, including muscle weakness, accumulation of tubular aggregates, a shift in myofiber type composition and nuclei mispositioning in myofibers. Using animals with muscle specific Atg7 deletion (a model of autophagy inactivation), we demonstrated that the pathological features associated with MYTHO knockdown are independent of its role in regulating autophagy. CONCLUSION: We conclude that MYTHO is a central player in regulating skeletal muscle mass and integrity.
Original languageEnglish
JournalFASEB Journal
Publication statusPublished - 1 May 2022
Externally publishedYes

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