Journal Article

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

Knudsen, Jonas R., Dalbram, Emilie, Henríquez-Olguin, Carlos, Li, Zhencheng, Richter, Erik A., Jensen, Thomas E., Treebak, Jonas T., Holmdahl, Rikard, Raun, Steffen H., Jaimovich, Enrique, Sylow, Lykke

2019

Overview

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. Reactive oxygen species (ROS) stimulate GLUT4-mediated glucose transport following contraction of isolated muscle, but it is not clear if this occurs in vivo. Here, the authors show in human volunteers that exercise induces ROS increase in muscle and, using loss of-function animal models, they demonstrate that NOX2 is a major ROS source required to stimulate glucose uptake during exercise.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 14/34 / 42/35 / 49/109 / 631/443/319 / 631/45/607/1168 / 64/60 / 692/698/1671/1668/1973 / 82/29 / 82/51 / 96/1 / 96/34 / Adult / Animal models / Animals / Biosensors / Contraction / CYBB protein / Cytosol - metabolism / Ergometry / Fluorescent dyes / Fluorescent indicators / Glucose / Glucose - metabolism / Glucose transport / Glucose transporter / Glucose Transporter Type 4 - metabolism / Humanities and Social Sciences / Humans / Male / Mice / multidisciplinary / Muscle, Skeletal - cytology / Muscle, Skeletal - metabolism / Muscles / Musculoskeletal system / NAD(P)H oxidase / NADPH Oxidase 2 - metabolism / Oxidase / Oxidation-Reduction / p38 Mitogen-Activated Protein Kinases - metabolism / Phosphorylation / Physical Conditioning, Animal / Physical Exertion / Rac1 protein / Reactive oxygen species / Reactive Oxygen Species - metabolism / Science / Science (multidisciplinary) / Second messengers / Skeletal muscle / Translocation