Estrogen-Related Receptor-γ

Abstract

Tissue vascularization is tightly coupled to its oxidative capacity. This phenomenon is especially well characterized in skeletal muscle, which can be enriched in either oxidative slow-twitch or glycolytic fast-twitch myofibers.1,2 Slow-twitch muscles are characterized by high-oxidative-capacity fatigue-resistant (type I) fibers and dense vascularity. Conversely, fast-twitch (type II) muscles have lower oxidative capacity, with a less developed vascular network, and are fatigue sensitive.3 Different studies have well demonstrated that nuclear receptors including peroxisome proliferator–activated receptor-[alpha) (PPAR-α), PPAR-δ, and estrogen-related receptor-α (ERR-α), along with coregulators PPAR-γ coactivator-1α (PGC-1α), PGC-1β, and nuclear receptor-interacting protein 1 (RIP140), control fatty acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis in skeletal muscle4–10; however, the mechanisms linking the oxidative profile of the muscle to its vasculature remain a matter of major interest. Article, see p 1087 A large number of proangiogenic growth factors that coordinate endothelial cell activation, proliferation, and migration and pericyte recruitment have been described in the skeletal muscle (reviewed in Carmeliet11 and Ferrara and Kerbel12). Whether nuclear receptors orchestrate the vascularization of aerobic muscles was unclear until recently. Two factors, the coactivator PGC-1α and the AMP kinase (AMPK), have drawn attention. PGC-1α is induced by hypoxia and exercise13 and represents a potential target to stimulate vascularization; however, PGC-1α knockout mice are viable, retain oxidative muscle, and have normal vasculature.13,14 Because the …