Bingfei Li, Wei Xiang, Wanwan Qi, Xinxin Liu, Weiwen Zhu, Wei Zhang, Runze Jin, Shuo Ma, Lifeng Chen, Chuanqing Bai, Shunzheng Fang, Jiangyi Wu, Xiaoqi Zhang, Limeng Dai, Xingying Guan, Jia Li, Song Li, Yan Xiong, Xiangqin Fang, Changyue Gao, Siru Zhou, Hong Guo, Zhenhong Ni
The clinical use of glucocorticoids often leads to skeletal muscle injury, characterized by muscle atrophy and dysfunction. Fibro-adipogenic progenitors (FAPs) play an important role in maintaining muscle homeostasis, but their roles in the recovery of skeletal muscle after glucocorticoid-induced injury remain largely elusive. Here, we reveal that glucocorticoid induces cellular senescence of FAPs, leading to their accumulation in skeletal muscle. Mechanistically, glucocorticoid enhances the expression of GFPT2 through STAT5A, which further elevates O-GlcNAcylation in FAPs and promotes their senescence. Targeting the STAT5A-GFPT2-mediated O-GlcNAcylation can reduce the burden of senescent FAPs in glucocorticoid-treated muscle and facilitate muscle recovery after injury. Our results demonstrate that exosomes derived from senescent FAPs suppress myotube formation, greatly inhibiting the regrowth of glucocorticoid-treated skeletal muscle. Moreover, senescent FAPs reduce the muscle stem cells (MuSCs) pool by suppressing their proliferation, thereby impairing the regenerative capacity of skeletal muscle during the recovery process after glucocorticoid treatment.