NOX2 is a major ROS source in exercising muscle regulating glucose uptake

Abstract

Reactive oxygen species (ROS) are increasingly recognized as key regulators of cellular metabolism. In skeletal muscle, ROS has been linked to glucose transport in isolated electrically stimulated muscles but the exact source of ROS in the context of in vivo exercise and whether it controls in vivo glucose uptake by glucose transporter 4 (GLUT4) is unknown. Here, we utilized a combination of genetically-encoded biosensors, fluorescent dyes and mouse models lacking the NADPH oxidase 2 (NOX2) regulatory subunits p47phox and Rac1 to demonstrate that NOX2 is the predominant source of ROS during in vivo treadmill exercise in skeletal muscle. Furthermore, p47phox-deficient mice phenocopy key aspects of metabolic dysregulation in Rac1 mKO mice, including decreased in vivo glucose uptake and GLUT4 translocation. These findings provide strong evidence that NOX2 is a major ROS source during in vivo exercise and its activity is crucial to the translocation of GLUT4 to increase glucose uptake.