Autophagy is a critical process for maintaining skeletal muscle mass, function, and integrity.
The molecular mechanisms regulating autophagy are complex and remain only partially 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 upregulated in several murine models of skeletal muscle atrophy. Short-term depletion of MYTHO in mice attenuates muscle atrophy induced by fasting, denervation, cancer cachexia, and sepsis. Conversely, MYTHO overexpression is sufficient to trigger muscle atrophy, whereas MYTHO reduction leads to a progressive increase in muscle mass, associated with sustained activation of the mTORC1 signaling pathway.
Long-term MYTHO depletion results in severe myopathic features, including impaired autophagy, muscle weakness, myofiber degeneration, and profound ultrastructural abnormalities such as accumulation of autophagic vacuoles and tubular aggregates. Pharmacological inhibition of the mTORC1 pathway using rapamycin alleviates the myopathic phenotype caused by MYTHO knockdown.
Skeletal muscles from human patients diagnosed with type 1 myotonic dystrophy (DM1) display reduced Mytho expression, mTORC1 pathway activation, and defective autophagy, suggesting that decreased Mytho expression may contribute to disease progression.
We conclude that MYTHO is a key regulator of autophagy and skeletal muscle integrity.
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