Marchildon F, Fu D, Lala-Tabbert N, Wiper-Bergeron N
Graduate Program in Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Cell Death Dis. 2016 Feb 25;7(2):e2109. doi: 10.1038/cddis.2016.4.
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.
CCAAT/增强子结合蛋白β（C/EBPβ）是一种在肌肉卫星细胞（SCs）中表达的转录因子，它抑制肌源性程序，并在分化早期下调。在一个条件性敲除模型中，配对盒蛋白7阳性（Pax7+）SCs中的C/EBPβ表达被敲低，尽管对照同窝小鼠的肌肉再生效率很高，但心脏毒素（CTX）损伤的修复效果很差。虽然缺乏C/EBPβ的成肌细胞在培养中能有效分化，但CTX损伤后再生不良归因于Pax7+细胞群比正常小，这并非由于SCs增殖失败。相反，缺乏C/EBPβ的肌肉中凋亡SCs的百分比增加。鉴于在没有C/EBPβ的情况下，氯化钡诱导的损伤比对照修复效率更高，我们研究了氯化钡和CTX损伤后的炎症反应，发现促炎细胞因子白细胞介素-1β（IL-1β）的水平在CTX损伤后显著升高，并且能在成肌细胞中诱导C/EBPβ表达。成肌细胞中高水平的C/EBPβ表达与对凋亡刺激的抗性相关，而其缺失增加了对毒胡萝卜素诱导的细胞死亡的敏感性。以癌症恶病质作为慢性炎症的模型，我们发现荷瘤恶病质动物的SCs和成肌细胞中C/EBPβ表达增加。此外，在Pax7+细胞中缺乏C/EBPβ的恶病质条件性敲除动物中，SCs区室因凋亡增加而减少，再生受损。我们的研究结果表明，肌肉损伤后以及癌症恶病质中IL-1β对C/EBPβ表达的刺激作用是促进SCs存活，因此是SCs和成肌细胞面对炎症时的一种保护机制。
