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

  • 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.
Author:Matthew Hancock, Anne D. Hafstad, Adam A. Nabeebaccus, Norman Catibog, Angela Logan, Ioannis Smyrnias, Synne S. Hansen, Johanna Lanner, Katrin SchröderORCiDGND, Michael P. MurphyORCiDGND, Ajay M. ShahORCiD, Min ZhangORCiD
Pubmed Id:
Parent Title (English):eLife
Publisher:eLife Sciences Publications
Place of publication:Cambridge
Contributor(s):Milica Radisic
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/12/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/01/10
Tag:Nfe2l2; Nox4; Research article; exercise; human biology and medicine; mitochondria; mouse; reactive oxygen species
Page Number:16
First Page:1
Last Page:16
Copyright Hancock et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0