The aging of the immune system, or immunosenescence, was recently verified to have a causal role in driving the aging of solid organs, while the senolytic elimination of senescent immune cells was found to effectively delay systemic aging. Our recent study also showed that immune cells in severely dystrophic muscles develop senescence-like phenotypes, including the increased expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Here we further investigated whether the specific clearance of senescent immune cells in dystrophic muscle may effectively improve the function of muscle stem cells and the phenotypes of dystrophic muscle. We observed increased percentage of senescent cells in macrophages from mdx/utro(−/−) mice (a murine model for muscular dystrophy disease, dystrophin−/−; utrophin−/−), while the treatment of mdx/utro(−/−) macrophages with senolytic drug fisetin resulted in reduced number of senescent cells. We administrated fisetin to mdx/utro(−/−) mice for 4 weeks, and observed obviously reduced number of senescent immune cells, restored number of muscle cells, and improve muscle phenotypes. In conclusion, our results reveal that senescent immune cells, such as macrophages, are greatly involved in the development of muscle dystrophy by impacting the function of muscle stem cells, and the senolytic ablation of these senescent cells with fisetin can be an effective therapeutic strategy for improving function of muscle stem cells and phenotypes of dystrophic muscles.

中文翻译：

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衰老巨噬细胞的衰老消除可恢复严重营养不良肌肉中的肌肉干细胞功能

免疫系统的老化或免疫衰老最近被证实在推动实体器官老化方面具有因果作用，而衰老免疫细胞的衰老消除被发现可有效延缓全身衰老。我们最近的研究还表明，严重营养不良的肌肉中的免疫细胞会出现类似衰老的表型，包括衰老相关分泌表型 (SASP) 因子和衰老标记物的表达增加。在这里，我们进一步研究了营养不良肌肉中衰老免疫细胞的特异性清除是否可以有效改善肌肉干细胞的功能和营养不良肌肉的表型。我们观察到来自mdx的巨噬细胞中衰老细胞的百分比增加/utro(−/−) 小鼠（肌营养不良症的小鼠模型，抗肌萎缩蛋白−/−；utrophin−/−），而用衰老药物非瑟酮处理mdx /utro(−/−) 巨噬细胞导致衰老细胞。我们给mdx /utro(−/−) 小鼠施用非瑟酮 4 周，观察到衰老免疫细胞数量明显减少，肌肉细胞数量恢复，肌肉表型改善。总之，我们的研究结果表明，衰老的免疫细胞（例如巨噬细胞）通过影响肌肉干细胞的功能而极大地参与了肌肉营养不良的发展，并且用非瑟酮对这些衰老细胞进行的衰老消融可能是一种有效的治疗策略改善肌肉干细胞的功能和营养不良肌肉的表型。