The Role And Mechanism Of FoxM1 In Skeletal Muscle Development And Regeneration

Skeletal muscle is an important motor organ in mammals,accounting for about 40% of the total human mass.The growth and repair of skeletal muscle after injury are of great significance to the maintenance of normal physiological function of human body.Muscle satellite cells(Muscle satellite cells,SCs)are adult stem cells with long-term self-renewal and differentiation potential in the skeletal muscle system,originating from the embryonic mesoderm.In mature individuals,SCs are located between the basement membrane and muscle cell membrane,and most of them are in quiescence.When the muscle is stimulated by injury,SCs are activated and begin to proliferate.Part of the proliferated SCs continues to differentiate into muscle cells and form muscle bundles to repair muscle tissue damages,while the other parts return to quiescence to maintain the SC pool.It can be seen that the balance transformation of SCs between quiescence,proliferation and differentiation is critical for the maintenance of SC pool and muscle homeostasis.Recent studies have revealed that a variety of transcription factors,non-coding RNA,kinases and apparent modification factors play an important role in the regulation of SCs function,but the internal regulatory network of SCs has not been fully analyzed.Therefore,in-depth mining of the molecular network regulating SCs will help to deepen the understanding of the maintenance of SCs function and skeletal muscle growth and development.FoxM1(Forkhead box protein M1),a member of the forkhead frame protein family,has been identified as a proto-oncogene,which plays an important role in cell proliferation and tumorigenesis.Existing studies had revealed that FoxM1 mainly regulates the expression of cell cycle-related genes through transcription,and then promotes G1/S phase and G2/M phase transition.Recent studies have confirmed that FoxM1 also plays an important role in the regulation of stem cell function.Studies have found that FoxM1 is specifically and highly expressed in human embryonic stem cells and protects human embryonic stem cells from oxidative stress and maintains their pluripotency by transcriptional regulation of Ccnb1 and Cdk1 expression.In addition,it has been reported that FoxM1 can maintain the quiescence of hematopoietic stem cells by transcriptional regulation of Nurr1,indicating that the function and related mechanisms of FoxM1 in different stem cells are heterogeneous.In previous studies,we found that FoxM1 was specifically highly expressed in SCs,and that knock down FoxM1 in myoblast cell line C2C12 significantly hindered cell proliferation,suggesting that FoxM1 plays an important regulatory role in the maintenance of SCs function.However,the exact function and mechanism of FoxM1 in SCs is not clear,and its role in skeletal muscle development and regeneration is also unknown.In order to explore the regulatory effect of Fox M1 on skeletal muscle and SCs function,we developed skeletal muscle specific FoxM1 knockout mice.We found that the absence of FoxM1 can lead to the loss of skeletal muscle in mice and seriously hinder the repair of skeletal muscle after injury.Further study found that FoxM1 mainly affects the maintenance of skeletal muscle by regulating SCs.According to the results of transcriptome sequence and ChIP-PCR,we found that FoxM1 promotes the proliferation of SCs through direct transcriptional regulation of Ccnb1.In addition,we also found that FoxM1 can inhibit Wnt/ ?-catenin signal by transcriptional regulation of Apc,and finally maintain the ability of SCs to repair damaged skeletal muscle.In this study,we reported the role of FoxM1 in the maintenance of SCs function and skeletal muscle homeostasis,confirmed the mechanism of FoxM1 regulating SCs cell cycle through transcriptional regulation of Ccnb1,and revealed the mechanism of FoxM1 suppressing Wnt/ ?-catenin signal by transcriptional regulation of Apc in SCs.This study reveals for the first time the role of Fox M1 in the regulation of SCs function and the maintenance of skeletal muscle homeostasis,expands the internal regulatory molecular network of SCs,and helps to deepen the understanding of skeletal muscle system functions' maintenance.