Exercise and PGC-1α-Independent Synchronization of Type I Muscle Metabolism and Vasculature by ERRγ

SummaryHow type I skeletal muscle inherently maintains high oxidative and vascular capacity in the absence of exercise is unclear. We show that nuclear receptor ERRγ is highly expressed in type I muscle and, when transgenically expressed in anaerobic type II muscles (ERRGO mice), dually induces metabolic and vascular transformation in the absence of exercise. ERRGO mice show increased expression of genes promoting fat metabolism, mitochondrial respiration, and type I fiber specification. Muscles in ERRGO mice also display an activated angiogenic program marked by myofibrillar induction and secretion of proangiogenic factors, neovascularization, and a 100% increase in running endurance. Surprisingly, the induction of type I muscle properties by ERRγ does not involve PGC-1α. Instead, ERRγ genetically activates the energy sensor AMPK in mediating the metabovascular changes in ERRGO mice. Therefore, ERRγ represents a previously unrecognized determinant that specifies intrinsic vascular and oxidative metabolic features that distinguish type I from type II muscle.

► ERRγ directs exercise-independent oxidative metabolism and neovascularization
► ERRγ transformation of sedentary muscle is independent of PGC-1α
► ERRγ promotes robust AMPK activation in the absence of exercise
► ERRγ transgenesis confers running endurance and resistance to diet-induced obesity