Leduc-Gaudet 2023 Nat Commun
|Leduc-Gaudet JP, Franco-Romero A, Cefis M, Moamer A, Broering FE, Milan G, Sartori R, Chaffer TJ, Dulac M, Marcangeli V, Mayaki D, Huck L, Shams A, Morais JA, Duchesne E, Lochmuller H, Sandri M, Hussain SNA, Gouspillou G (2023) MYTHO is a novel regulator of skeletal muscle autophagy and integrity. https://doi.org/10.1038/s41467-023-36817-1|
» Nat Commun 14:1199. PMID: 36864049 Open Access
Leduc-Gaudet Jean-Philippe, Franco-Romero Anais, Cefis Marina, Moamer Alaa, Broering Felipe E, Milan Giulia, Sartori Roberta, Chaffer Tomer Jordi, Dulac Maude, Marcangeli Vincent, Mayaki Dominique, Huck Laurent, Shams Anwar, Morais Jose A, Duchesne Elise, Lochmuller Hanns, Sandri Marco, Hussain Sabah NA, Gouspillou Gilles (2023) Nat Commun
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.
Labels: MiParea: Respiration, Genetic knockout;overexpression
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS Pathway: N, NS, ROX HRR: Oxygraph-2k, O2k-Fluorometer