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: Eijiro Yamada, Claire C Bastie, Hiroshi Koga, Yichen Wang, Ana Maria Cuervo, Jeffrey E Pessin
• Journal: Cell reports (Cell Rep) Vol. 1 Issue 5 Pg. 557-69 (May 31 2012) ISSN: 2211-1247 [Electronic] United States
• PMID: 22745922 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Multiprotein Complexes
• Proteins
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Class III Phosphatidylinositol 3-Kinases
• Fyn protein, mouse
• Proto-Oncogene Proteins c-fyn
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases

Topics

• Animals
• Apoptosis (physiology)
• Autophagy (physiology)
• Class III Phosphatidylinositol 3-Kinases (physiology)
• Disease Models, Animal
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, Transgenic
• Multiprotein Complexes
• Muscle Fibers, Skeletal (pathology)
• Muscle Weakness (pathology, physiopathology)
• Muscular Atrophy (physiopathology)
• Phenotype
• Proteins (physiology)
• Proto-Oncogene Proteins c-fyn (genetics, physiology)
• STAT3 Transcription Factor (physiology)
• Signal Transduction (physiology)
• TOR Serine-Threonine Kinases