ERR? Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1?/?-Deficient Muscle.

ABSTRACT: PGC1? 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 ERR?. To decipher their epistatic relationship, we explored ERR? gain of function in muscle-specific PGC1?/? double-knockout (PKO) mice. ERR?-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 PGC1?/?. Furthermore, in combination with voluntary exercise, ERR? 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 PGC1?/? regulates both innate and adaptive energy metabolism.

SUBMITTER: Fan W 

PROVIDER: S-EPMC5860878 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature