Myocardial NADPH oxidase-4 regulates the physiological response to acute exercise.
Matthew HancockAnne D HafstadAdam A NabeebaccusNorman CatibogAngela LoganIoannis SmyrniasSynne S HansenJohanna LannerKatrin SchroderMichael P MurphyAjay M ShahMin ZhangPublished in: eLife (2018)
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.
Keyphrases
- oxidative stress
- high intensity
- physical activity
- left ventricular
- resistance training
- reactive oxygen species
- transcription factor
- dna damage
- healthcare
- heart failure
- high fat diet induced
- ischemia reperfusion injury
- induced apoptosis
- type diabetes
- skeletal muscle
- public health
- liver failure
- mental health
- risk assessment
- intensive care unit
- respiratory failure
- insulin resistance
- drug induced
- social media
- health information
- anti inflammatory
- heat shock