Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity

Estrogen-related receptor γ (ERRγ), a member of the ERR family of orphan nuclear hormone receptors, was described to play a role a critical role in the perinatal switch to oxidative metabolism in the myocardium. In addition to the heart, ERRγ is expressed in tissues and cell types that have a high metabolic activity. We show that ERRγ regulates the expression of genes regulating oxidative phosphorylation, fatty acid oxidation, angiogenesis and skeletal muscle fiber type and contractile function. Further, we wanted to understand the functional consequence of ERRγ expression in skeletal muscle. Transgenic mice expressing a VP16ERRγ under the regulation of the muscle creatine kinase promoter, demonstrate an increase in exercise capacity as compared to their wildtype littermates. Despite a decrease in muscle size, mitochondrial function, as assessed by activity of key mitochondrial enzymes, was increased in these mice. Further, the peak oxidative capacity was higher in the transgenics, and the mice were able to maintain a lower respiratory exchange ratio under this exercise regimen. In contrast, mice lacking one copy of ERRγ, have a decrease in exercise capacity and muscle mitochondrial function. Interestingly, it was observed that increased ERRγ in muscle appears to generate a gene expression profile that is similar to that of “red oxidative fiber type”. We demonstrate that a small molecule agonist of ERRbeta/gamma can increase mitochondrial function in mouse myotubes. Our data indicate that ERRγ plays an important role in causing a shift toward slow twitch muscle and oxidative metabolism in skeletal muscle, and concomitantly, a greater capacity for endurance exercise. Thus, the activation of this nuclear receptor provides a potential node for therapeutic intervention for diseases such as obesity, which is associated with reduced oxidative metabolism and a lower type I fiber content in skeletal muscle