Estrogen-Related Receptor Alpha Promotes Skeletal Muscle Regeneration and Mitigates Muscular Dystrophy

Area of Science:

• Muscle biology
• Regenerative medicine
• Molecular endocrinology

Background:

• Duchenne Muscular Dystrophy (DMD) presents insurmountable challenges in skeletal muscle regeneration.
• Estrogen-related receptor alpha (ERRα) is crucial for skeletal muscle metabolism and fitness.

Purpose of the Study:

• To investigate the role of ERRα signaling in muscle regeneration and Duchenne Muscular Dystrophy (DMD).
• To determine if ERRα activation can mitigate dystrophy in DMD models.

Main Methods:

• Utilized pre-clinical models of acute muscle injury and DMD (mdx mice).
• Investigated ERRα expression in C2C12 myoblasts and regenerating muscle.
• Performed RNA sequencing on ERRα knockdown cells.
• Overexpressed ERRα in rodent skeletal muscle and in mdx mice.

Main Results:

• ERRα is induced during muscle differentiation and regeneration.
• ERRα knockdown impaired myoblast proliferation and differentiation.
• ERRα overexpression enhanced regeneration, angiogenesis, and mitochondrial biogenesis after injury.
• ERRα and its target genes were suppressed in dystrophic muscle stem cells (MuSCs) from mdx mice.
• Muscle-specific ERRα overexpression in mdx mice restored gene expression, improved vascular and oxidative remodeling, reduced muscle damage, enhanced regeneration, and improved function.

Conclusions:

• ERRα plays a pro-regenerative role in skeletal muscle.
• ERRα deficiency contributes to pathology in dystrophic muscles and MuSCs.
• ERRα activation represents a potential therapeutic strategy for DMD via angio-metabolic gene programming.