A Cdh1-FoxM1-Apc axis controls muscle development and regeneration

Area of Science:

• Muscle biology
• Molecular genetics
• Cellular signaling

Background:

• Forkhead box M1 (FoxM1) is a transcription factor vital for cell proliferation, self-renewal, and cancer.
• Its role in endogenous muscle development and regeneration is not well understood.

Purpose of the Study:

• To investigate the function of FoxM1 in muscle satellite cell (SC) biology.
• To elucidate the molecular mechanisms by which FoxM1 regulates muscle regeneration.

Main Methods:

• Conditional knockout of FoxM1 in mouse muscle satellite cells.
• Analysis of muscle regeneration following injury.
• Western blotting and gene expression analysis.
• Studies involving Cdh1 knockout and FoxM1 haploinsufficiency.

Main Results:

• Loss of FoxM1 in SCs leads to muscle atrophy and impaired regeneration.
• FoxM1 directly activates Adenomatous Polyposis Coli (Apc) expression, inhibiting Wnt/β-catenin signaling.
• FoxM1 overexpression enhances myogenesis but impairs regeneration by promoting SC exhaustion via Cyclin B1 (Ccnb1) regulation.
• Cdh1-mediated degradation of FoxM1 is essential for SC quiescence; Cdh1 loss depletes SCs.
• FoxM1 haploinsufficiency rescues regeneration defects in Cdh1 knockout mice.

Conclusions:

• The Cdh1-FoxM1-Apc signaling axis is a critical regulator of muscle development and regeneration.
• FoxM1 acts as a key mediator controlling SC activation, proliferation, and exhaustion.
• Targeting this axis may offer therapeutic strategies for muscle degenerative diseases.