ERRα overexpression in mdx mice improved muscle regeneration and function.
ERRα is critical for muscle metabolism and fitness, and its activation may enhance muscle regeneration.
Silencing ERRα in muscle cells reduced their ability to proliferate and differentiate.
In pre-clinical models, ERRα overexpression improved angiogenesis and mitochondrial function following muscle injury.
Muscle stem cells from dystrophic mdx mice showed decreased ERRα and target gene expression, leading to defects in cell proliferation and differentiation.
Restoring ERRα expression in mdx mice improved angiogenic and metabolic gene expression, alleviated muscle damage, and enhanced regeneration.
Simplified
Skeletal muscle regeneration in chronic muscle diseases such as (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 BaClinjury, 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. 2
Key numbers
4×
Increase in Regenerating Myofibers
ERRα transgenic mice vs. wild-type mice at 4 days post-injury.
7–19
Decrease in Serum CK Levels
Comparison of serum creatine kinase levels in mdx vs. mdx-TG mice.
6
Higher Total Torque Production
Total torque output during fatigue tests in mdx-TG vs. mdx mice.
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