title: CCAAT/enhancer binding protein beta protects muscle satellite cells from apoptosis after injury and in cancer cachexia.
abstract: CCAAT/enhancer binding protein beta (C/EBPβ), a transcription factor expressed in muscle satellite cells (SCs), inhibits the myogenic program and is downregulated early in differentiation. In a conditional null model in which C/EBPβ expression is knocked down in paired box protein 7+ (Pax7+) SCs, cardiotoxin (CTX) injury is poorly repaired, although muscle regeneration is efficient in control littermates. While myoblasts lacking C/EBPβ can differentiate efficiently in culture, after CTX injury poor regeneration was attributed to a smaller than normal Pax7+ population, which was not due to a failure of SCs to proliferate. Rather, the percentage of apoptotic SCs was increased in muscle lacking C/EBPβ. Given that an injury induced by BaCl2 is repaired with greater efficiency than controls in the absence of C/EBPβ, we investigated the inflammatory response following BaCl2 and CTX injury and found that the levels of interleukin-1β (IL-1β), a proinflammatory cytokine, were robustly elevated following CTX injury and could induce C/EBPβ expression in myoblasts. High levels of C/EBPβ expression in myoblasts correlated with resistance to apoptotic stimuli, while its loss increased sensitivity to thapsigargin-induced cell death. Using cancer cachexia as a model for chronic inflammation, we found that C/EBPβ expression was increased in SCs and myoblasts of tumor-bearing cachectic animals. Further, in cachectic conditional knockout animals lacking C/EBPβ in Pax7+ cells, the SC compartment was reduced because of increased apoptosis, and regeneration was impaired. Our findings indicate that the stimulation of C/EBPβ expression by IL-1β following muscle injury and in cancer cachexia acts to promote SC survival, and is therefore a protective mechanism for SCs and myoblasts in the face of inflammation.
authors.affiliation: Graduate Program in Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Marchildon
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Fu
authors.affiliation: Graduate Program in Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Lala-Tabbert
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Wiper-Bergeron
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017609:Barium Compounds / Q000633:toxicity; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D054715:Cardiotoxins / Q000633:toxicity; D002460:Cell Line; D002712:Chlorides / Q000633:toxicity; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D051763:PAX7 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019284:Thapsigargin / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017609:Barium Compounds; D022782:CCAAT-Enhancer-Binding Protein-beta; D054715:Cardiotoxins; D002712:Chlorides; D053583:Interleukin-1beta; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D012333:RNA, Messenger; C024986:barium chloride; D019284:Thapsigargin