Cell biology

Biology

Glycolysis

Cytosol

Reactive oxygen species

Endocrinology

Metabolism

Biochemistry

Skeletal muscle

Insulin

Mitochondrial ROS

Glucose uptake

Intracellular

Ex vivo

NADPH oxidase

In vitro

Enzyme

Internal medicine

Medicine

Glucose transporter

Chemistry

GLUT4

Nature Communications

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.

Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise