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

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

Marchildon F F Fu D D Lala-Tabbert N N Wiper-Bergeron N N

Cell death & disease 20160225

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 p ...[more]

PMID: 26913600

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Project description:UnlabelledDuchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is the most common muscular dystrophy. Characterized by rounds of muscle degeneration and regeneration, DMD features progressive muscle wasting and is fatal. One approach for treatment is transplantation of muscle progenitor cells to repair and restore dystrophin expression to damaged muscle. However, the success of this approach has been limited by difficulties in isolating large numbers of myogenic progenitors with strong regenerative potential, poor engraftment, poor survival of donor cells, and limited migration in the diseased muscle. We demonstrate that induction of the transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) using the cyclic adenosine monophosphate phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) results in enhanced myoblast expansion in culture and increased satellite cell marker expression. When equal numbers of IBMX-treated cells were transplanted into dystrophic muscle, they contributed to muscle repair more efficiently than did vehicle-treated cells and engrafted into the satellite cell niche in higher numbers, demonstrating improved cell migration from the site of injury and enhanced survival after transplantation. Thus, pharmacologic stimulation of C/EBPβ expression reprograms myoblasts to a more stem cell-like state, promotes expansion in culture, and improves engraftment such that better transplantation outcomes are achieved.SignificanceDuchenne muscular dystrophy is a genetic disorder for which no cure exists. One therapeutic approach is transplantation of myogenic progenitors to restore dystrophin to damaged muscle, but this approach is limited by poor engraftment of cultured myoblasts. Transient upregulation of CCAAT/enhancer-binding protein β in primary myoblasts using the phosphodiesterase isobutylmethylxanthine (IBMX) increases satellite cell marker expression in cultured myoblasts, improves their migration, and increases their survival after transplantation. When transplanted into C57BL/10ScSn-mdx/J mice , IBMX-treated myoblasts restored dystrophin expression and were able to occupy the satellite cell niche more efficiently than controls. A myoblast culture approach that reprograms myoblasts to a more primitive state, resulting in improved transplantation outcomes and reinvigorating research into myoblast transplantation as a viable therapeutic approach, is described.

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

Publications

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

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