title: Mouse skeletal muscle fiber-type-specific macroautophagy and muscle wasting are regulated by a Fyn/STAT3/Vps34 signaling pathway.
abstract: Skeletal muscle atrophy induced by aging (sarcopenia), inactivity, and prolonged fasting states (starvation) is predominantly restricted to glycolytic type II muscle fibers and typical spares oxidative type I fibers. However, the mechanisms accounting for muscle fiber-type specificity of atrophy have remained enigmatic. In the current study, although the Fyn tyrosine kinase activated the mTORC1 signaling complex, it also induced marked atrophy of glycolytic fibers with relatively less effect on oxidative muscle fibers. This was due to inhibition of macroautophagy via an mTORC1-independent but STAT3-dependent reduction in Vps34 protein levels and decreased Vps34/p150/Beclin1/Atg14 complex 1. Physiologically, in the fed state endogenous Fyn kinase activity was increased in glycolytic but not oxidative skeletal muscle. In parallel, Y705-STAT3 phosphorylation increased with decreased Vps34 protein levels. Moreover, fed/starved regulation of Y705-STAT3 phosphorylation and Vps34 protein levels was prevented in skeletal muscle of Fyn null mice. These data demonstrate a Fyn/STAT3/Vps34 pathway that is responsible for fiber-type-specific regulation of macroautophagy and skeletal muscle atrophy.
authors: Department of Medicine, Albert Einstein College of Medicine, Diabetes Research and Training Center, Bronx, NY 10461, USA.
authors: Eijiro
authors: E
authors: Yamada
authors: Claire C
authors: CC
authors: Bastie
authors: Hiroshi
authors: H
authors: Koga
authors: Yichen
authors: Y
authors: Wang
authors: Ana Maria
authors: AM
authors: Cuervo
authors: Jeffrey E
authors: JE
authors: Pessin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D058546:Class III Phosphatidylinositol 3-Kinases / Q000502:physiology*; D004195:Disease Models, Animal; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D018908:Muscle Weakness / Q000473:pathology / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000503:physiopathology; D010641:Phenotype; D011506:Proteins / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D058546:Class III Phosphatidylinositol 3-Kinases; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases