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

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.

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

“…The beneficial effects of exercise partly depend on the improvement in mitochondrial function, including increases in mitochondrial biogenesis and improved respiratory capacity [70]. The beneficial effects of exercise, at least in part, seem to be mediated by ROS signaling [71], as they are mitigated by antioxidants such as vitamin C [72] or suppressed by ROS-metabolizing enzymes [73]; however, ROS appear to derive not from the ETC, but likely from other sources, such as NOX. One of the beneficial effects of exercise is the increase in antioxidant enzymes.…”

“…Indeed, several beneficial effects of exercise in the vasculature and skeletal muscle, such as increased physical activity, are diminished in NOX4-knockout mice [81]. Furthermore, Hancock et al conclusively demonstrated that Nrf2 activation by AES is mediated by NOX4 and contributes to mitochondrial quality control using cardiomyocyte-specific knockout of NOX4 and Nrf2 (csNrf2 KO) [73]. Both ADP-limited and maximal OxPhos capacity are significantly decreased in csNrf2-KO mice only after exercise.…”

“…Thus, it is plausible that ROS and NO that are generated at multiple sites are responsible for Nrf2 activation, but p62 phosphorylation may mediate ROS signaling to activate Nrf2 in oxidative muscles. [73,75]. NOX4 induced by AES localizes to various organelles, including the plasma membrane, nucleus, endoplasmic reticulum (ER), and especially mitochondria, in the heart and produces ROS to activate Nrf2 [78][79][80].…”

“…NOX4 induced by AES localizes to various organelles, including the plasma membrane, nucleus, endoplasmic reticulum (ER), and especially mitochondria, in the heart and produces ROS to activate Nrf2 [78][79][80]. The AES-induced decrease in mtROS is inhibited by Nrf2 deficiency but rescued by the mitochondria-targeted antioxidant MitoQ [73].…”

Metformin increases tauroursodeoxycholic acid levels to improve insulin resistance in diet-induced obese mice

“…In vitro , we found that TUDCA could act as an agonist of the Nrf2/ARE signaling pathway. This is reminiscent of the expression pattern of Nrf2, a crucial stress regulator to reduce the ROS, which is a key factor in sensitizing insulin signaling 55–57 . It has also been confirmed that up-regulation of the Nrf2 expression both by genetic manipulation and pharmacological interference, can significantly decrease the content of ROS and ameliorate IR and T2D 58,59 .…”