Myocardial NADPH oxidase-4 regulates the physiological response to acute exercise
Open accessAbstract
Regular exercise has widespread health benefits. Fundamental to these beneficial effects is the ability of the heart to intermittently and substantially increase its performance without incurring damage, but the underlying homeostatic mechanisms are unclear. We identify the ROS-generating NADPH oxidase-4 (Nox4) as an essential regulator of exercise performance in mice. Myocardial Nox4 levels increase during acute exercise and trigger activation of the transcription factor Nrf2, with the induction of multiple endogenous antioxidants. Cardiomyocyte-specific Nox4-deficient (csNox4KO) mice display a loss of exercise-induced Nrf2 activation, cardiac oxidative stress and reduced exercise performance. Cardiomyocyte-specific Nrf2-deficient (csNrf2KO) mice exhibit similar compromised exercise capacity, with mitochondrial and cardiac dysfunction. Supplementation with an Nrf2 activator or a mitochondria-targeted antioxidant effectively restores cardiac performance and exercise capacity in csNox4KO and csNrf2KO mice respectively. The Nox4/Nrf2 axis therefore drives a hormetic response that is required for optimal cardiac mitochondrial and contractile function during physiological exercise.
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Deletion of NOX4 in cardiomyocytes impairs heart function and exercise endurance.
“whereas more recent studies have shown that the deletion of NOX4 in cardiomyocytes impairs heart function and exercise endurance (39).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [39]
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- Authors
- Hancock, M., Hafstad, A. D., Nabeebaccus, A. A., Catibog, N., Logan, A., Smyrnias, I., Hansen, S. S., Lanner, J., Schröder, K., Murphy, M. P., Shah, A. M., & Zhang, M.
- Affiliations
- King's College London (GB)
- UiT The Arctic University of Norway (NO)
- University of Cambridge (GB)
- Karolinska Institutet (SE)
- Goethe University Frankfurt (DE)
- Corresponding author
- Shah, Ajay M
- Zhang, Min
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-12-27
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6307857
- OpenAlex
- W2908432291
- Cited by
- 64
- References
- 46
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 12 · 2023: 9 · 2022: 4 · 2021: 11 · 2020: 11 · 2019: 6
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Research Portal (King's College London) (submittedVersion, cc-by)
- NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Norwegian Health Association (6412)
- Medical Research Council (MC_U105663142)
- Wellcome (110159/Z/ 15/Z)
- British Heart Foundation (PG/12/26/29477, RG/13/11/30384, CH/1999001/1173)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- NOX4, Nrf2, acute exercise, exercise capacity, myocardium, reactive oxygen species, oxidative stress, cardiomyocytes, hormesis, mitochondrial dysfunction, cardiac contractile function, antioxidants, mitochondria-targeted antioxidants, Nrf2 activators
- MeSH terms
- NADPH Oxidase 4, Animals, Antioxidants, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Myocardium, Physical Conditioning, Animal, Physiological Phenomena, Signal Transduction, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Myocytes, Cardiac, NF-E2-Related Factor 2
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