Estrogen-Related Receptor α Inverse Agonist Enhances Basal Glucose Uptake in Myotubes through Reactive Oxygen Species

Estrogen-related receptors alpha (ERR alpha) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) function coordinately to regulate mitochondrial biogenesis and oxidative phosphorylation particularly in muscle tissue. In this study, we addressed the consequences of suppressing the activity of ERR alpha in L6 myotubes using an ERRa inverse agonist XCT-790. We found that treating differentiated L6 myotubes with XCT-790 reduced the expression of PGG-1 alpha and suppressed mitochondrial biogenesis. Additionally, XCT-790 increased the production of reactive oxygen species (ROS) which in turn induced the expressions of glucose transporters 1, 2, and 5 leading to an increase in glucose uptake and uncoupling protein 3 leading to a reduction of mitochondrial membrane potential. Thus, suppressing the activity of ERRa which is primarily responsible for controlling beta-oxidation would nonetheless indirectly affect glucose uptake in a ROS-dependent manner.