CCAAT/enhancer binding protein beta protects muscle satellite cells from apoptosis after injury and in cancer cachexia

• Published in: Cell death & disease Vol. 7; no. 2; p. e2109
• Main Authors: Marchildon, F, Fu, D, Lala-Tabbert, N, Wiper-Bergeron, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.02.2016; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/106; 14/63; 631/250/256; 631/45/612/822; 631/80/82/23; 64/60; 692/4023/1671; 82/1; 82/51; 96/2; 96/21; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Barium Compounds - toxicity; Biochemistry; Biomedical and Life Sciences; Cancer; Cardiotoxins - toxicity; CCAAT-Enhancer-Binding Protein-beta - deficiency; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Biology; Cell Culture; Cell Line; Cellular biology; Chlorides - toxicity; Immunohistochemistry; Immunology; Interleukin-1beta - metabolism; Life Sciences; Mice; Mice, Knockout; Mice, Transgenic; Myoblasts - cytology; Myoblasts - metabolism; Neoplasms - metabolism; Neoplasms - pathology; Original; original-article; PAX7 Transcription Factor - genetics; PAX7 Transcription Factor - metabolism; Proteins; RNA, Messenger - metabolism; Thapsigargin - toxicity; Up-Regulation - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2016.4

CCAAT/enhancer binding protein beta (C/EBP β ), 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 β 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 β 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 β . Given that an injury induced by BaCl 2 is repaired with greater efficiency than controls in the absence of C/EBP β , we investigated the inflammatory response following BaCl 2 and CTX injury and found that the levels of interleukin-1 β (IL-1 β ), a proinflammatory cytokine, were robustly elevated following CTX injury and could induce C/EBP β expression in myoblasts. High levels of C/EBP β 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 β expression was increased in SCs and myoblasts of tumor-bearing cachectic animals. Further, in cachectic conditional knockout animals lacking C/EBP β 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 β expression by IL-1 β 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.