Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise
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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.
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Defective NOX2 activation, due to loss of function mutations in the regulatory p47phox subunit, or the inducible deletion of the NOX2 subunit Rac1 in adult mice, does not alter skeletal muscle mitochondrial content.
“However, defective NOX2 activation, due to loss of function mutations in the regulatory p47phox subunit (23), or the inducible deletion of the NOX2 subunit Rac1 in adult mice (28), does not alter skeletal muscle mitochondrial content.”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [23]
H2O2 production in the mitochondrial matrix during exercise may actually be decreased.
“H2O2 production in the mitochondrial matrix during exercise may actually be decreased (23).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [23]
NOX2 is activated and contributes to skeletal muscle cytosolic ROS generation and glucose uptake during moderate-intensity exercise.
“whereas others have shown that NOX2 is activated and contributes to skeletal muscle cytosolic ROS generation and glucose uptake during moderate-intensity exercise (23).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [23]
Although NOX2 may be required for the promotion of glucose uptake during exercise, it is not important for exercise-induced hormetic responses that enhance muscle function, nor is it required for eliciting long-lasting insulin-sensitizing effects.
“Thus, although NOX2 may be required for the promotion of glucose uptake during exercise, it is not important for exercise-induced hormetic responses that enhance muscle function, nor is it required for eliciting long-lasting insulin-sensitizing effects.”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [23]
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References 45 · Cited by 228
- Authors
- Henríquez-Olguin, C., Knudsen, J. R., Raun, S. H., Li, Z., Dalbram, E., Treebak, J. T., Sylow, L., Holmdahl, R., Richter, E. A., Jaimovich, E., & Jensen, T. E.
- Affiliations
- University of Copenhagen (DK)
- Karolinska Institutet (SE)
- University of Chile (CL)
- Corresponding author
- Jensen, Thomas E.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-10-11
- Volume
- 10
- Issue
- 1
- Pages
- 4623-4623
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6789013
- OpenAlex
- W2980184266
- Cited by
- 228
- References
- 45
- Citations by year
- 2026: 30 · 2025: 34 · 2024: 29 · 2023: 27 · 2022: 24 · 2021: 45 · 2020: 33 · 2019: 5
- FWCI
- 18.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Danish Diabetes Academy
- Cancerfonden
- Lundbeckfonden (R289-2018-1935, R208-2015-3388)
- Novo Nordisk (15182, NNF18OC0032082)
- Vetenskapsrådet
- Danmarks Frie Forskningsfond (400400233, 6108-00203)
- Novo Nordisk Fonden (#15182, NNF15OC0015182, NNF18OC0034072, NNF16OC0023418, NNF18OC0032082)
- Comisión Nacional de Investigación Científica y Tecnológica
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- reactive oxygen species, NADPH oxidase 2, NOX2, skeletal muscle, physical activity, glucose uptake, GLUT4 translocation, glucose transport, p47phox, Rac1, moderate-intensity exercise
- MeSH terms
- NADPH Oxidase 2, Adult, Animals, Cytosol, Physical Exertion, Glucose, Humans, Male, Oxidation-Reduction, Phosphorylation, Physical Conditioning, Animal, Ergometry, Reactive Oxygen Species, Muscle, Skeletal, p38 Mitogen-Activated Protein Kinases, Glucose Transporter Type 4, Mice
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