Axin1 Suppresses Muscle Regeneration by Promoting Myoblast Proliferation and Inhibiting Differentiation

Area of Science:

• Muscle physiology and regeneration
• Cellular biology
• Metabolic disease research

Background:

• Axin1 is a scaffold protein involved in glucose homeostasis and muscle function.
• Its specific role in skeletal muscle growth and regeneration is not well understood.
• Investigating Axin1 is important in the context of insulin resistance and obesity.

Purpose of the Study:

• To investigate the role of Axin1 in skeletal muscle cell proliferation, differentiation, and regeneration.
• To explore Axin1's function under conditions of insulin resistance and obesity.
• To elucidate the molecular mechanisms underlying Axin1's effects on muscle cells.

Main Methods:

• Utilized C2C12 muscle cells for in vitro studies, including Axin1 knockdown and overexpression.
• Administered chronic insulin treatment to simulate insulin resistance.
• Employed adeno-associated virus-mediated short interfering RNA (AAV-siAxin1) in mouse models.
• Analyzed protein and mRNA levels of key muscle regulatory factors (Cyclin D1, MyoD, MyoG, MyHC, Pax7, eMyHC, Desmin).
• Studied skeletal muscle regeneration in high-fat diet (HFD)-fed mice and db/db mice.

Main Results:

• Axin1 knockdown inhibited proliferation and promoted differentiation of C2C12 cells by decreasing Cyclin D1 and increasing MyoG/MyHC.
• Axin1 overexpression had opposite effects.
• Chronic insulin treatment increased Axin1, promoting proliferation and impairing differentiation; Axin1 knockdown reversed this.
• AAV-siAxin1 enhanced MyoG levels in mouse skeletal muscle.
• HFD and db/db mice showed higher Axin1 and lower MyoG/eMyHC/Desmin, correlating with impaired regeneration.
• Axin1 knockdown ameliorated HFD-induced deficits in muscle regeneration.

Conclusions:

• Down-regulation of Axin1 inhibits muscle cell proliferation and promotes differentiation in basal and insulin-resistant states.
• Axin1 plays a detrimental role in skeletal muscle regeneration in obesity models.
• Targeting Axin1 could be a therapeutic strategy for improving muscle health in metabolic diseases.