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

TitleMyocardial NADPH oxidase-4 regulates the physiological response to acute exercise.
Publication TypeJournal Article
Year of Publication2018
AuthorsHancock, M, Hafstad, AD, Nabeebaccus, AA, Catibog, N, Logan, A, Smyrnias, I, Hansen, SS, Lanner, J, Schröder, K, Murphy, MP, Shah, AM, Zhang, M
Date Published2018 12 27

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.

Alternate JournalElife
Citation Key10.7554/eLife.41044
PubMed ID30589411
PubMed Central IDPMC6307857
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
RG/13/11/30384 / / British Heart Foundation / United Kingdom
CH/1999001/11735 / / British Heart Foundation / United Kingdom
PG/12/26/29477 / / British Heart Foundation / United Kingdom
CH/1999001/1173 / / British Heart Foundation / United Kingdom
/ / Wellcome Trust / United Kingdom
110159/Z/ 15/Z / / Wellcome Trust / United Kingdom