title: The E3 ubiquitin ligase TRAF6 intercedes in starvation-induced skeletal muscle atrophy through multiple mechanisms.
abstract: Starvation, like many other catabolic conditions, induces loss of skeletal muscle mass by promoting fiber atrophy. In addition to the canonical processes, the starvation-induced response employs many distinct pathways that make it a unique atrophic program. However, in the multiplex of the underlying mechanisms, several components of starvation-induced atrophy have yet to be fully understood and their roles and interplay remain to be elucidated. Here we unveiled the role of tumor necrosis factor receptor-associated factor 6 (TRAF6), a unique E3 ubiquitin ligase and adaptor protein, in starvation-induced muscle atrophy. Targeted ablation of TRAF6 suppresses the expression of key regulators of atrophy, including MAFBx, MuRF1, p62, LC3B, Beclin1, Atg12, and Fn14. Ablation of TRAF6 also improved the phosphorylation of Akt and FoxO3a and inhibited the activation of 5' AMP-activated protein kinase in skeletal muscle in response to starvation. In addition, our study provides the first evidence of the involvement of endoplasmic reticulum stress and unfolding protein response pathways in starvation-induced muscle atrophy and its regulation through TRAF6. Finally, our results also identify lysine 63-linked autoubiquitination of TRAF6 as a process essential for its regulatory role in starvation-induced muscle atrophy.
authors.affiliation: Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Pradyut K
authors.initials: PK
authors.lastname: Paul
authors.forename: Shephali
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Vivek
authors.initials: V
authors.lastname: Mishra
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.forename: Bryant G
authors.initials: BG
authors.lastname: Darnay
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D013217:Starvation / Q000150:complications; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D000074050:TWEAK Receptor; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D044767:Ubiquitin-Protein Ligases