Acute exercise stress promotes Ref1/Nrf2 signalling and increases mitochondrial antioxidant activity in skeletal muscle

Abstract

New Findings r What is the central question of this study?How does acute exercise affect the redox effector factor-1 (Ref1) and nuclear factor erythroid 2-related factor 2 (Nrf2) signalling and its association with mitochondrial H 2 O 2 production and antioxidant capacity? r What is the main finding and its importance?Ref1/Nrf2 signalling in skeletal muscles was activated by acute exercise, and this activation was correlated with increased mitochondrial H 2 O 2 content and antioxidant capacity (reduced glutathione and manganese superoxide dismutase). The finding indicates that the oxidative stress induced by acute exercise in skeletal muscle mitochondria is associated with the upregulation of Ref1/Nrf2 signalling and enhancement of antioxidant defense pathways. This mechanism may play a role in preventing cellular oxidative stress resistance during acute exercise.The molecular mechanism of exercise-induced oxidative stress and adaptive activation of antioxidant responses in skeletal muscle has not been fully elucidated. This study aimed to investigate the effect of acute exercise on redox effector factor-1 (Ref1) and nuclear factor erythroid 2-related factor 2 (Nrf2) signalling and associations with mitochondrial H 2 O 2 production and antioxidant mechanisms in skeletal muscles. Groups of male ICR/CD-1 mice were subjected to an acute exercise bout of different durations (45, 90, 120 or 150 min). Muscle tissues (gastrocnemius and quadriceps femoris) were harvested after exercise to measure mitochondrial manganese superoxide dismutase (MnSOD) and copper-zinc superoxide dismutase (CuZnSOD) activities, reduced glutathione (GSH) content and expression of Ref1/Nrf2 genes and Ref1/Nrf2 proteins. The acute exercise increased oxidative stress and activated Ref1/Nrf2 signalling in a time-dependent manner, with a linear correlation between the mitochondrial H 2 O 2 content and Ref1/Nrf2 expressions. The GSH content and MnSOD activity were also significantly increased, but CuZnSOD activity was not significantly affected. The findings indicate that the H 2 O 2 production induced by acute exercise in skeletal muscle mitochondria in the mouse is closely associated with upregulation of the Ref1/Nrf2 signalling

Nrf2 mediates redox adaptations to exercise

“…A single bout of acute exercise in wild-type mice has been shown to increase Nrf2 gene expression [36], [40] as well as Nrf2 protein abundance in skeletal muscle [40] and Nrf2-dependent phase II enzymes [36], [41]. Two additional studies that measured the effects of exercise on Nrf2 signaling in mouse myocardium are essentially in agreement with the data from skeletal muscle [42], [43].…”

“…Treadmill exercise lasting less than one hour elicited no change in Nrf2 mRNA, or protein expression [40], [49], [50]. As duration was increased to 90-min or more, Nrf2 activation became apparent in both skeletal muscle tissue and in brain homogenate with significant increases in Nrf2 protein expression in skeletal muscle and gene expression increasing in both tissues [40], [49]. In an extreme example of endurance exercise, Li and colleagues [50] demonstrated no difference in Nrf2 activity in mice running for 1-h on the treadmill, but robust increases in Nrf2 nuclear accumulation and Nrf2-ARE binding following a 6-h session on the treadmill.…”

“…Treadmill exercise lasting less than one hour elicited no change in Nrf2 mRNA, or protein expression [40], [49], [50]. As duration was increased to 90-min or more, Nrf2 activation became apparent in both skeletal muscle tissue and in brain homogenate with significant increases in Nrf2 protein expression in skeletal muscle and gene expression increasing in both tissues [40], [49].…”

“…However, Wang et al [40] found a positive correlation between exercise-induced mitochondrial H 2 O 2 content and Nrf2 gene expression and Nrf2 protein expression (measured in response to exercise of different duration). However, under the assumption that higher intensity induces greater oxidative stress; these data along with the results from the electrical pulse stimulation in myotubes suggest that intensity may affect Nrf2 signaling.…”

Dietary vitamin B6 modulates the gene expression of myokines, Nrf2-related factors, myogenin and HSP60 in the skeletal muscle of rats

“…Nrf2/ARE signalling is activated by acute exercise stress in the myocardium (14). Several previous studies have suggested that the role of Nrf2 goes beyond antioxidant mechanisms (15,16). Al-Sawaf et al (16) reported that Nrf2 regulated myogenic regulatory factor (Mrf) expression and that Nrf2-knockout retarded skeletal muscle regeneration after injury.…”