MYTHO is a novel regulator of skeletal muscle autophagy and integrity

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.

The autophagy inhibitor NSC185058 suppresses mTORC1-mediated protein anabolism in cultured skeletal muscle

“…The direct immediate applications of these findings may be narrow, but the implications for further investigation into the role of anabolism in health and disease are broad. Prior investigations have shown that autophagy support muscular adaptations to exercise training 27 , while other basic science studies support the notion that autophagy is required for the maintenance of muscle mass 5 , 6 . Those findings, along with our proposed mechanism, support the concept that autophagy and anabolism are inherently intertwined, and suggest that healthy growth and adaptation in skeletal muscle are likely driven by a complex interplay between the mTOR and autophagic pathways to promote anabolic adaptations.…”

“…Although we believe our proposed model to be a valuable improvement on how the relationship between mTORC1 and the autophagic cascade are viewed, there are undeniably many more aspects and implications that remain to be fully identified. For instance, the recent identification of the MYTHO protein as being required for muscle autophagy also demonstrates that MYTHO deletion leads to aberrant muscle growth and mTORC1 activation 6 , but also induces severe myopathy. This phenotype is reminiscent of myostatin deficiency, which leads to an increase in muscle mass but reductions in specific force and contractility 43 , and it may be salient to note that myostatin is a documented inducer of autophagy, including that of the ATG4B gene 44 .…”

“…However, despite the clear role of stimuli promoting mTOR (such as growth factors, exercise, or nutrient stimulation) in negatively regulating autophagy and the demonstrable induction of autophagy with mTOR inhibition, there is growing appreciation that autophagic signaling is in fact critical to cellular growth outside of the response to starvation. For instance, autophagy-deficient mice display profound muscle atrophy 5 , and the knockout of a newly-discovered autophagy gene, MYTHO, in mice leads to pathological changes in muscle, in spite of muscle hypertrophy 6 . Further, evidence suggests that autophagy is required for muscular adaptations to exercise, and that both the mTOR and autophagic pathways are enhanced in response to exercise training 7 , 8 .…”

Identification of ferroptosis-associated genes and potential pharmacological targets in sepsis-induced myopathy

“…The KEGG pathway analysis showed that the differentially expressed genes associated with Ferroptosis in sepsis-induced myopathy mainly contribute to pathways such as ferroptosis, autophagy, the p53 signaling pathway, the PI3K-Akt signaling pathway, the mTOR signaling pathway, the HIF-1α signaling pathway, endocrine resistance, and several cancer-related pathways. Autophagy has been recognized as a major regulatory mechanism and therapeutic target for reducing sepsis-induced muscle atrophy [ 27 , 28 ]. The activation of the PI3K-Akt signaling pathway has been shown to mitigate oxidative stress and decrease inflammation, consequently relieving muscle wasting caused by sepsis [ 16 , 29 ].…”

PRMT5 mediates FoxO1 methylation and subcellular localization to regulate lipophagy in myogenic progenitors

“… 22 , 23 Moreover, FoxO1 has also been implicated in regulating autophagy in skeletal muscle to maintain muscle mass and function, particularly during nutrient deprivation. 24 – 26 However, the mechanisms governing subcellular localization of FoxO1 in myogenic progenitors are not well understood.…”