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

ABSTRACT Skeletal muscle regeneration in chronic muscle diseases such as Duchenne Muscular Dystrophy (DMD) has remained clinically unsurmountable. Estrogen‐related receptor alpha (ERRα) plays a critical role in adult skeletal muscle metabolism and exercise fitness. Whether ERRα activation can drive muscle regeneration and mitigate dystrophy in DMD is not known. We have investigated ERRα signaling in pre‐clinical models of acute muscle injury and DMD. ERRα is induced in differentiating C2C12 myoblast and regenerating muscle. ERRα silencing suppressed proliferation and differentiation in C2C12 myoblasts. RNA sequencing revealed that angiogenic factor and proliferation genes were downregulated by ERRα knockdown in proliferating cells, whereas oxidative mitochondrial and differentiation regulator genes were downregulated in differentiating cells. In accordance with in vitro findings, transgenic ERRα overexpression in rodent skeletal muscle stimulates muscle regeneration after acute BaCl 2 injury, which is accompanied by enhanced angiogenesis and mitochondrial biogenesis. Notably, ERRα and its angiogenic and metabolic target gene expression is suppressed in muscle stem cells (MuSCs) derived from dystrophic muscles in mdx mice, coinciding with proliferation and differentiation defects in these cells. Loss of ERRα and its target gene expression was recapitulated in adult dystrophic mdx muscles. Consequently, muscle specific ERRα overexpression in mdx mice restored angiogenic and metabolic gene expression, induced vascular and oxidative remodeling, alleviated baseline muscle damage, boosted regeneration in dystrophic muscle and improved function. Our studies demonstrate a pro‐regenerative role of ERRα and its deficiency in dystrophic muscles and MuSCs. ERRα activation could be a therapeutic strategy for DMD through angio‐metabolic gene programming.