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Elife. 2018 Dec 27;7. pii: e41044. doi: 10.7554/eLife.41044.

Myocardial NADPH oxidase-4 regulates the physiological response to acute exercise.

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School of Cardiovascular Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom.
Cardiovascular Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Institut für Kardiovaskuläre Physiologien, Goethe-Universität, Frankfurt, Germany.


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.


Nfe2l2; Nox4; exercise; human biology; medicine; mitochondria; mouse; reactive oxygen species

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