title: Reciprocal interaction between TRAF6 and notch signaling regulates adult myofiber regeneration upon injury.
abstract: Skeletal muscle is a postmitotic tissue that repairs and regenerates through activation of a population of stem-cell-like satellite cells. However, signaling mechanisms governing adult skeletal muscle regeneration remain less understood. In the present study, we have investigated the role of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein involved in receptor-mediated activation of multiple signaling pathways in regeneration of adult myofibers. Skeletal muscle-specific depletion of TRAF6 in mice (TRAF6(mko)) improved regeneration of myofibers upon injury with a concomitant increase in the number of satellite cells and activation of the Notch signaling pathway. Ex vivo cultures of TRAF6(mko) myofiber explants demonstrated an increase in the proliferative capacity of myofiber-associated satellite cells accompanied by an upregulation of Notch ligands. Deletion of TRAF6 also inhibited the activity of transcription factor NF-κB and the expression of inflammatory cytokines and augmented the M2c macrophage phenotype in injured muscle tissues. Collectively, our study demonstrates that specific inhibition of TRAF6 improves satellite cell activation and skeletal muscle regeneration through upregulation of Notch signaling and reducing the inflammatory repertoire.
authors.affiliation: Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: Sajedah M
authors.initials: SM
authors.lastname: Hindi
authors.forename: Pradyut K
authors.initials: PK
authors.lastname: Paul
authors.forename: Saurabh
authors.initials: S
authors.lastname: Dahiya
authors.forename: Vivek
authors.initials: V
authors.lastname: Mishra
authors.forename: Shephali
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000293:injuries* / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D016328:NF-kappa B / Q000276:immunology; D051880:Receptors, Notch / Q000378:metabolism*; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D051880:Receptors, Notch; D048029:TNF Receptor-Associated Factor 6