CCAAT/enhancer binding protein beta protects muscle satellite cells from apoptosis after injury and in cancer cachexia.
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ABSTRACT: CCAAT/enhancer binding protein beta (C/EBP?), 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/EBP? 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/EBP? 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/EBP?. Given that an injury induced by BaCl2 is repaired with greater efficiency than controls in the absence of C/EBP?, we investigated the inflammatory response following BaCl2 and CTX injury and found that the levels of interleukin-1? (IL-1?), a proinflammatory cytokine, were robustly elevated following CTX injury and could induce C/EBP? expression in myoblasts. High levels of C/EBP? 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/EBP? expression was increased in SCs and myoblasts of tumor-bearing cachectic animals. Further, in cachectic conditional knockout animals lacking C/EBP? in Pax7+ cells, the SC compartment was reduced because of increased apoptosis, and regeneration was impaired. Our findings indicate that the stimulation of C/EBP? expression by IL-1? 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.
SUBMITTER: Marchildon F
PROVIDER: S-EPMC4849162 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
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