Abstract
Cells turn on autophagy, an intracellular recycling pathway, when deprived of nutrients. How autophagy is regulated by hormonal signals in response to major changes in metabolic state is not well understood. Here, we provide evidence that myonectin (CTRP15), a skeletal muscle-derived myokine, is a novel regulator of cellular autophagy. Starvation activated liver autophagy, whereas nutrient supplementation following food deprivation suppressed it; the former and latter correlated with reduced and increased expression and circulating levels of myonectin, respectively, suggestive of a causal link. Indeed, recombinant myonectin administration suppressed starvation-induced autophagy in mouse liver and cultured hepatocytes, as indicated by the inhibition of LC3-dependent autophagosome formation, p62 degradation, and expression of critical autophagy-related genes. Reduction in protein degradation is mediated by the PI3K/Akt/mTOR signaling pathway; inhibition of this pathway abrogated the ability of myonectin to suppress autophagy in cultured hepatocytes. Together, our results reveal a novel skeletal muscle-liver axis controlling cellular autophagy, underscoring the importance of hormone-mediated tissue cross-talk in maintaining energy homeostasis.
Highlights
Liver autophagy is dynamically regulated in fed and fasted states
To evaluate which macronutrients could prevent the suppression of myonectin expression in nutrient-deprived cells, C2C12 myotubes were incubated in autophagic medium in the presence or absence of 5 mM glucose and/or a mixture of minimal essential amino acids
The effects on myonectin expression were much greater if both glucose and essential amino acids were given to cells, reflecting the additive effects of both nutrients
Summary
Results: Myonectin is secreted by skeletal muscle in response to nutrient availability, and it activates the mTOR signaling pathway to suppress autophagy in liver. Our results reveal a novel skeletal muscle-liver axis controlling cellular autophagy, underscoring the importance of hormone-mediated tissue cross-talk in maintaining energy homeostasis. The anabolic hormone insulin, secreted in response to food intake, and dietderived amino acids suppress hepatocyte autophagy by activating the nutrient-sensing mTOR (mammalian target of rapamycin) signaling pathway [15]. Insulin and glucagon play an important role in regulating cellular autophagy in the fed and fasted states, respectively, other hormonal signals may affect this recycling process. Myonectin Regulates Liver Autophagy autophagy in liver, highlighting its role in mediating skeletal muscle-liver cross-talk to modulate metabolic processes critical to maintaining tissue homeostasis
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