Endothelin-1 impairs skeletal muscle myogenesis and development via ETB receptors and p38 MAPK signaling pathway

Area of Science:

• Muscle physiology
• Molecular biology
• Aging research

Background:

• Myopenia, characterized by muscle mass and strength decline, is linked to aging and obesity, increasing fall and fracture risks.
• Skeletal muscle wasting involves reduced myoblasts, impaired regeneration, and increased atrophy markers (Atrogin-1, MuRF-1).
• Elevated Endothelin-1 (ET-1) levels in aging correlate with fibrosis and strength loss, but its role in myogenesis and atrophy is unclear.

Purpose of the Study:

• To investigate the effects of ET-1 on myoblast proliferation, differentiation, and development.
• To elucidate the molecular mechanisms underlying ET-1's impact on skeletal muscle.
• To assess the in vivo consequences of ET-1 on muscle function and performance.

Main Methods:

• Utilized C2C12 myoblast cell cultures to study ET-1's effects on proliferation and differentiation.
• Employed ET-1-infused mice to model chronic exposure and evaluate muscle atrophy and performance.
• Investigated signaling pathways including ETB receptors, p38 MAPK, and proteasome activity.

Main Results:

• ET-1 significantly reduced insulin-stimulated C2C12 myoblast proliferation via ETB receptors.
• ET-1 inhibited myoblast differentiation, decreasing MyoD, MyoG, and MyHC expression through ETB receptors and p38 MAPK.
• Chronic ET-1 infusion in mice led to skeletal muscle atrophy and impaired exercise performance.

Conclusions:

• ET-1 inhibits insulin-induced myoblast proliferation and myogenesis via ETB receptors and the p38 MAPK pathway.
• ET-1 induces skeletal muscle atrophy by decreasing MyHC expression and promoting protein degradation.
• Targeting ET-1 signaling may offer therapeutic strategies for myopenia and age-related muscle decline.