ERRa fosters running endurance by driving myofiber aerobic transformation and fuel efficiency

Objective: Estrogen related receptor a (ERRa) occupies a central node in the transcriptional control of energy metabolism, including in skeletal muscle, but whether modulation of its activity can directly contribute to extend endurance to exercise remains to be investigated. The goal of this study was to characterize the benefit of mice engineered to express a physiologically relevant activated form of ERRa on skeletal muscle exercise metabolism and performance. Methods: We recently shown that mutational inactivation of three regulated phosphosites in the amino terminal domain of the nuclear receptor ERRa impedes its degradation, leading to an accumulation of ERRa proteins and perturbation of metabolic homeostasis in ERRa3SA mutant mice. Herein, we used a multi-omics approach in combination with physical endurance tests to ascertain the consequences of expressing the constitutively active phospho-deficient ERRa3SA form on muscle exercise performance and energy metabolism. Results: Genetic heightening of ERRa activity enhanced exercise capacity, fatigue-resistance, and endurance. This phenotype resulted from extensive reprogramming of ERRa global DNA occupancy and transcriptome in muscle leading to an increase in oxidative fibers, mitochondrial biogenesis, fatty acid oxidation, and lactate homeostasis. Conclusion: Our findings support the potential to enhance physical performance and exercise-induced health benefits by targeting molecular pathways regulating ERRa transcriptional activity. Overall design: ChIP-seq analysis of liver or skeletal muscle isolated from WT and ERRa 3SA phospho-mutant mice on a C57BL/6N genetic background.