ERRγ Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-Deficient Muscle

PGC1α is a pleiotropic co-factor that affects angiogenesis, mitochondrial biogenesis, and oxidative muscle remodeling via its association with multiple transcription factors, including the master oxidative nuclear receptor ERRγ. To decipher their epistatic relationship, we explored ERRγ gain of function in muscle-specific PGC1α/β double-knockout (PKO) mice. ERRγ-driven transcriptional reprogramming largely rescues muscle damage and improves muscle function in PKO mice, inducing mitochondrial biogenesis, antioxidant defense, angiogenesis, and a glycolytic-to-oxidative fiber-type transformation independent of PGC1α/β. Furthermore, in combination with voluntary exercise, ERRγ gain of function largely restores mitochondrial energetic deficits in PKO muscle, resulting in a 5-fold increase in running performance. Thus, while PGC1s can interact with multiple transcription factors, these findings implicate ERRs as the major molecular target through which PGC1α/β regulates both innate and adaptive energy metabolism. [Display omitted] •ERRγ rescues muscle damage in PGC1α/β-deficient muscle•Mitochondrial energetic defects in PGC1α/β-KO muscle are improved by ERRγ•ERRγ induces oxidative muscle remodeling and angiogenesis in PGC1α/β knockout mice•Exercise and ERRγ individually and cooperatively alleviate defects in PGC1 KO muscle Fan et al. demonstrate that ERRγ improves mitochondrial energy metabolism in PGC1α/β-deficient muscle through its direct activation of target genes. Such ERRγ-induced effects are further boosted in combination with exercise training, suggesting ERRs are the major transcriptional modulator through which PGC1α/β regulates both innate and adaptive energy metabolism.