title: Proinflammatory cytokine tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) suppresses satellite cell self-renewal through inversely modulating Notch and NF-κB signaling pathways.
abstract: Satellite cell self-renewal is an essential process to maintaining the robustness of skeletal muscle regenerative capacity. However, extrinsic factors that regulate self-renewal of satellite cells are not well understood. Here, we demonstrate that TWEAK cytokine reduces the proportion of Pax7(+)/MyoD(-) cells (an index of self-renewal) on myofiber explants and represses multiple components of Notch signaling in satellite cell cultures. The number of Pax7(+) cells is significantly increased in skeletal muscle of TWEAK knock-out (KO) mice compared with wild-type in response to injury. Furthermore, Notch signaling is significantly elevated in cultured satellite cells and in regenerating myofibers of TWEAK-KO mice. Forced activation of Notch signaling through overexpression of the Notch1 intracellular domain (N1ICD) rescued the TWEAK-mediated inhibition of satellite cell self-renewal. TWEAK also activates the NF-κB transcription factor in satellite cells and inhibition of NF-κB significantly improved the number of Pax7(+) cells in TWEAK-treated cultures. Furthermore, our results demonstrate that a reciprocal interaction between NF-κB and Notch signaling governs the inhibitory effect of TWEAK on satellite cell self-renewal. Collectively, our study demonstrates that TWEAK suppresses satellite cell self-renewal through activating NF-κB and repressing Notch signaling.
authors.affiliation: From the Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky 40202 and.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ogura
authors.forename: Vivek
authors.initials: V
authors.lastname: Mishra
authors.forename: Sajedah M
authors.initials: SM
authors.lastname: Hindi
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051763:PAX7 Transcription Factor / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics / Q000502:physiology; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; D018836:Inflammation Mediators; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D016328:NF-kappa B; C497762:Notch1 protein, mouse; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D051881:Receptor, Notch1; D011994:Recombinant Proteins; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors
keywords: Cytokine Action; Inflammation; NF-κB; Notch Pathway; Signaling; Skeletal Muscle; Stem Cells; TWEAK, Satellite Cells, Self-renewal, Notch; Tumor Necrosis Factor (TNF)