title: Skeletal muscle-derived myonectin activates the mammalian target of rapamycin (mTOR) pathway to suppress autophagy in liver.
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.
authors.affiliation: From the Department of Physiology and Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Seldin
authors.forename: Xia
authors.initials: X
authors.lastname: Lei
authors.forename: Stefanie Y
authors.initials: SY
authors.lastname: Tan
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Stanson
authors.forename: Zhikui
authors.initials: Z
authors.lastname: Wei
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D019587:Dietary Supplements; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000166:cytology*; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013217:Starvation / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; C572502:Erfe protein, mouse; C490981:Gtf2h1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009124:Muscle Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; Liver; Liver Metabolism; Skeletal Muscle; mTOR