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

Matthew Hancock,Synne S Hansen,Ioannis Smyrnias,Michael P Murphy,Angela Logan,Adam A Nabeebaccus,Ajay M Shah,Min Zhang,Anne D Hafstad,Katrin Schröder,Norman Catibog,Johanna Lanner

doi:10.7554/elife.41044

Abstract

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.

Highlights

Regular physical exercise has widespread beneficial effects on multiple body systems in healthy individuals and increases quality of life and lifespan
It was previously shown that NADPH oxidase-4 (Nox4) mRNA and protein levels are low in the adult mouse heart but are upregulated by chronic hemodynamic overload (Zhang et al, 2010)
The multiple beneficial effects of regular exercise depend upon the ability of the healthy heart to safely and consistently increase its contractile performance during the periods when cardiac output and overall body oxygen consumption are elevated

Summary

Introduction

Regular physical exercise has widespread beneficial effects on multiple body systems in healthy individuals and increases quality of life and lifespan. Excessive levels of ROS (oxidative stress) could cause damage to membranes, proteins and DNA and lead to detrimental consequences such as mitochondrial, metabolic and cellular dysfunction These potentially detrimental effects are limited by endogenous antioxidant defences, and exercise has been found to increase antioxidant capacity in the heart and skeletal muscle (Powers et al, 2014; Radak et al, 2017). It is not known whether Nox plays any physiological role in the heart. We report that cardiomyocyte Nox is an essential mediator of the physiological activation of the Nrf pathway during acute exercise, triggering an adaptive response that preserves redox balance, mitochondrial function and exercise performance. Our findings identify a novel physiological pathway that is required for the heart to safely and efficiently support physical exercise

Results

Discussion

Materials and methods