Nrf2 mediates redox adaptations to exercise

Abstract

The primary aim of this review is to summarize the current literature on the effects of acute exercise and regular exercise on nuclear factor erythroid 2-related factor 2 (Nrf2) activity and downstream targets of Nrf2 signaling. Nrf2 (encoded in humans by the NFE2L2 gene) is the master regulator of antioxidant defenses, a transcription factor that regulates expression of more than 200 cytoprotective genes. Increasing evidence indicates that Nrf2 signaling plays a key role in how oxidative stress mediates the beneficial effects of exercise. Episodic increases in oxidative stress induced through bouts of acute exercise stimulate Nrf2 activation and when applied repeatedly, as with regular exercise, leads to upregulation of endogenous antioxidant defenses and overall greater ability to counteract the damaging effects of oxidative stress. The evidence of Nrf2 activation in response to exercise across variety of tissues may be an important mechanism of how exercise exerts its well-known systemic effects that are not limited to skeletal muscle and myocardium. Additionally there are emerging data that results from animal studies translate to humans.

Keywords: Acute exercise; Cell signaling; HO-1; NFE2L2; Phase II enzymes; Reactive oxygen species; Regular exercise; SOD.

Graphical abstract

Fig. 1

Nrf2 signaling. Nrf2 is activated by exercise-induced ROS or phytonutrient Nrf2 activators. Antioxidant supplementation inhibits the signaling of exercise-induced ROS and thereby downstream Nrf2 signaling.

Fig. 2

Exercise induces increased Nrf2 at the whole-cell level, but nuclear accumulation is attenuated in older adults. Nrf2 response to exercise in the whole cell [A] and nuclear fraction [B] of PBMCs. Values are means±SEM. Representative blots of changes in Nrf2 and loading control in young (Y) and older (O) are provided above the corresponding graphs. There was a significant main effect of time in fold change of whole-cell Nrf2 (P=0.003). Nuclear accumulation only increased significantly in the young, but not the older group (main effect of age, P=0.031). Reprinted from with permission from Elsevier.

Fig. 3

Exercise training with antioxidant vitamin supplementation inhibits training adaptations while Nrf2 activators enhance training effects. Rodents trained with concomitant vitamin C supplementation failed to improve their time to exhaustion relative to sedentary control mice [A]. In direct contrast, rats supplemented with an Nrf2 activating compound during their training program performed significantly better in a time to exhaustion test relative to both sedentary controls and the non-supplemented exercise group suggesting a potential synergistic effect [B]. Data adapted from Gomez-Cabrera et al. and Kumar et al. .