Mouse Skeletal Muscle Fiber-Type-Specific Macroautophagy and Muscle Wasting Are Regulated by a Fyn/STAT3/Vps34 Signaling Pathway

• Published in: Cell reports (Cambridge) Vol. 1; no. 5; pp. 557 - 569
• Main Authors: Yamada, Eijiro, Bastie, Claire C., Koga, Hiroshi, Wang, Yichen, Cuervo, Ana Maria, Pessin, Jeffrey E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.05.2012; Elsevier
• Subjects: 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; Muscle Weakness - physiopathology; Muscular Atrophy - physiopathology; Phenotype; Proteins - physiology; Proto-Oncogene Proteins c-fyn - genetics; Proto-Oncogene Proteins c-fyn - physiology; Signal Transduction - physiology; STAT3 Transcription Factor - physiology; TOR Serine-Threonine Kinases; autophagy; STAT3; Fyn; Vps34; muscle atrophy; LKB1; mTORC1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.03.014

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. [Display omitted] ► Glycolytic muscle macroautophagy and atrophy occur independent of mTORC1 activation ► Muscle atrophy occurs through a STAT3/Vps34 signaling pathway ► Starvation inhibits STAT3 phosphorylation and increases expression of Vps34 protein Skeletal muscle mass is maintained by a dynamic balance between macromolecular synthesis and degradation that are controlled by multiple intracellular pathways in response to a variety of extracellular and intracellular cues. Macroautophagy plays a critical role in this process because genetic and developmental reduction in macroautophagy correlates with states of muscle wasting. This study by Pessin and colleagues demonstrates the presence of a Fyn/STAT3/Vps34 pathway that is responsible for glycolytic, but not oxidative, skeletal muscle-specific regulation of macroautophagy and muscle wasting.