STAT3 Regulates Adult Muscle Satellite Cell Maintenance During Injury-induced Muscle Regeneration

We previously showed that STAT3 regulates myoblast differentiation in cell culture models, yet its role in adult muscle satellite cells (MuSC) in vivo was less well characterized. When Stat3 was conditionally deleted in MuSC, muscle development and adult MuSC formation were not affected. However, with repeated muscle injuries, the number of the quiescent MuSC in STAT3-null mice decreased and the regeneration was delayed, suggesting defective MuSC maintenance. Consistently, when we conditionally deleted Stat3 in MuSC of dystrophin-null mice, a mouse model for the fatal human Duchenne muscular dystrophy, the adult double knockout (dKO) mice displayed age-dependent reduction in the number of MuSC, and increase in muscle inflammation and fibrosis. Mechanistically, Stat3 ablation in dystrophin-null MuSC resulted in downregulation of several key myogenic genes including Pax7, upregulation of multiple pro-inflammatory and pro-fibrotic genes, and an increase in fibroadipogenic progenitor cells, which collectively contributed to defective MuSC maintenance and aggravated inflammation and fibrosis in dKO mice.

此前我们已证实，信号转导与转录激活因子3（STAT3）可在细胞培养模型中调控成肌细胞分化，但该因子在成体肌肉卫星细胞（Muscle Satellite Cells, MuSC）体内的功能尚未得到充分阐明。当在MuSC中条件性敲除Stat3后，肌肉发育及成体MuSC的形成并未受到影响。但在反复肌肉损伤后，STAT3敲除小鼠体内静息态MuSC的数量减少，肌肉再生过程延迟，提示MuSC的维持功能存在缺陷。与此一致的是，当我们在肌营养不良蛋白敲除小鼠（该小鼠是致命性人类疾病杜氏肌营养不良症（Duchenne Muscular Dystrophy）的经典动物模型）的MuSC中条件性敲除Stat3时，成年双基因敲除（double knockout, dKO）小鼠表现出随年龄增长的MuSC数量减少，同时肌肉炎症与纤维化程度加重。从机制层面来看，在肌营养不良蛋白敲除的MuSC中敲除Stat3，会导致包括配对盒7（Pax7）在内的多个关键成肌相关基因表达下调，同时上调多种促炎及促纤维化基因，并增加纤维脂肪祖细胞（fibroadipogenic progenitor cells）的数量；上述变化共同导致了dKO小鼠MuSC维持功能缺陷，并加重了其肌肉炎症与纤维化程度。