Forkhead box M1 (FoxM1) transcriptional factor has a principal role in regulating cell proliferation, self-renewal, and tumorigenesis. However, whether FoxM1 regulates endogenous muscle development and regeneration remains unclear. Here we found that loss of FoxM1 in muscle satellite cells (SCs) resulted in muscle atrophy and defective muscle regeneration. FoxM1 functioned as a direct transcription activator of adenomatous polyposis coli (Apc), preventing hyperactivation of wnt/β-catenin signaling during muscle regeneration. FoxM1 overexpression in SCs promoted myogenesis but impaired muscle regeneration as a result of spontaneous activation and exhaustion of SCs by transcriptional regulation of Cyclin B1 (Ccnb1). The E3 ubiquitin ligase Cdh1 (also termed Fzr1) was required for FoxM1 ubiquitylation and subsequent degradation. Loss of Cdh1 promoted quiescent SCs to enter into the cell cycle and the SC pool was depleted by serial muscle injuries. Haploinsufficiency of FoxM1 ameliorated muscle regeneration of Cdh1 knock-out mice. These data demonstrate that the Cdh1–FoxM1–Apc axis functions as a key regulator of muscle development and regeneration.

叉头盒M1（FoxM1）转录因子在调节细胞增殖，自我更新和肿瘤发生中起主要作用。但是，FoxM1是否调节内源性肌肉发育和再生仍不清楚。在这里，我们发现肌肉卫星细胞（SCs）中FoxM1的丢失导致肌肉萎缩和肌肉再生不良。FoxM1用作腺瘤性息肉病大肠杆菌（Apc）的直接转录激活因子，可防止肌肉再生过程中wnt /β-catenin信号的过度激活。通过细胞周期蛋白B1（Ccnb1）的转录调控，SCs的自发激活和衰竭导致了SC中FoxM1的过表达促进了肌发生，但损害了肌肉的再生。E3泛素连接酶Cdh1（也称为Fzr1）是FoxM1泛素化和随后降解所必需的。Cdh1的丢失促进了静态SC进入细胞周期，并且SC池因一系列肌肉损伤而耗尽。FoxM1的单倍剂量不足改善了Cdh1基因敲除小鼠的肌肉再生。这些数据表明，Cdh1-FoxM1-Apc轴是肌肉发育和再生的关键调节器。