Abstract
Reactive oxygen species (ROS) act as intracellular compartmentalized second messengers, mediating metabolic stress-adaptation. In skeletal muscle fibers, ROS have been suggested to stimulate glucose transporter 4 (GLUT4)-dependent glucose transport during artificially evoked contraction ex vivo, but whether myocellular ROS production is stimulated by in vivo exercise to control metabolism is unclear. Here, we combined exercise in humans and mice with fluorescent dyes, genetically-encoded biosensors, and NADPH oxidase 2 (NOX2) loss-of-function models to demonstrate that NOX2 is the main source of cytosolic ROS during moderate-intensity exercise in skeletal muscle. Furthermore, two NOX2 loss-of-function mouse models lacking either p47phox or Rac1 presented striking phenotypic similarities, including greatly reduced exercise-stimulated glucose uptake and GLUT4 translocation. These findings indicate that NOX2 is a major myocellular ROS source, regulating glucose transport capacity during moderate-intensity exercise.
Highlights
Reactive oxygen species (ROS) act as intracellular compartmentalized second messengers, mediating metabolic stress-adaptation
We found that exercise stimulated an 86% increase in DCFH oxidation in human skeletal muscle (Fig. 1a), which was accompanied by an expected increase in the phosphorylation state of known exercise-responsive proteins (Fig. 1b)
Our results demonstrated that NADPH oxidase 2 (NOX2) was required for this shift and was a major cytosolic ROS source during moderate-intensity exercise
Summary
Reactive oxygen species (ROS) act as intracellular compartmentalized second messengers, mediating metabolic stress-adaptation. Two NOX2 loss-of-function mouse models lacking either p47phox or Rac[1] presented striking phenotypic similarities, including greatly reduced exercise-stimulated glucose uptake and GLUT4 translocation. These findings indicate that NOX2 is a major myocellular ROS source, regulating glucose transport capacity during moderate-intensity exercise. We took advantage of recent methodological developments in the redox signaling field, including a method for preservation of in vivo ROS modifications and genetically encoded ROS biosensors[18] This allowed us to measure both general and localized NOX2-specific ROS production in wild-type (WT) mice and mice lacking NOX2 activity due to the absence of either the Rac[1] or p47phox regulatory subunits. These results imply that NOX2 is a major source of ROS production during moderate-intensity exercise and that Rac[1] is required for GLUT4 translocation and glucose uptake due to its essential role in NOX2 activation
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