Muscle-derived TRAIL negatively regulates myogenic differentiation.

Area of Science:

• Muscle Biology
• Cell Signaling
• Apoptosis

Background:

• TNF-related apoptosis-inducing ligand (TRAIL) is recognized for inducing apoptosis in cancer cells.
• Non-apoptotic roles of TRAIL have been observed in various cell types.
• TRAIL and its receptor TRAIL-R2 are present in skeletal muscles, but their function in myogenesis is unknown.

Purpose of the Study:

• To investigate the role of muscle-derived TRAIL in skeletal myogenesis.
• To elucidate the mechanism by which TRAIL influences myogenic differentiation.

Main Methods:

• Utilized C2C12 myoblast cell culture for in vitro studies.
• Employed TRAIL and TRAIL-R2 knockdown and recombinant TRAIL treatments.
• Assessed myoblast differentiation, cell cycle exit, p21 expression, and ERK signaling.
• Investigated muscle regeneration in a mouse injury model.

Main Results:

• TRAIL knockdown enhanced C2C12 myoblast differentiation.
• Recombinant TRAIL inhibited p21 expression and suppressed cell cycle exit.
• Blocking cell cycle progression rescued differentiation inhibited by TRAIL.
• TRAIL knockdown improved muscle regeneration in mice.
• ERK pathway inhibition reversed TRAIL's inhibitory effects on p21 and differentiation.

Conclusions:

• TRAIL acts as an autocrine regulator of skeletal myogenesis.
• TRAIL inhibits myogenic differentiation by modulating cell cycle exit, potentially via ERK signaling.
• This study reveals a non-apoptotic, cell-autonomous function of TRAIL in skeletal muscle development and regeneration.