Acute and chronic exercise effects on NrF2 and antioxidants in the muscle and brain tissue of Sprague Dawley rats

Nuclear factor erythroid 2 related factor 2 (NrF2), is an essential transcription factor and a master regulator of the antioxidant defense system, which increases antioxidants in response to the production of reactive oxygen and nitrogen species (RONS). Disproportional increases in RONS compared to antioxidant defense capabilities can induce a state of oxidative stress (OS). Aerobic exercise of sufficient intensity and duration is well-known to increase the production of RONS in the blood, skeletal muscle and brain. Chronic aerobic exercise has been shown to mediate OS through increases in antioxidant factors. However, there are only two studies that have reported changes in NrF2 in response to aerobic exercise in a healthy cohort, but were limited to chronic exercise and examined the striatum brain region and whole brain only. The purpose of this study was to 1) determine the extent to which markers of OS (MDA, GSSG, GSSG/TGSH) change with acute aerobic exercise in the blood, skeletal muscle and brain, 2) determine the extent to which antioxidant defense factors (GSH, TGSH, Mn-SOD) change with chronic aerobic exercise in skeletal muscle and brain, and 3) determine the extent to which NrF2 protein concentration changes with acute and chronic aerobic exercise in skeletal muscle and specific brain regions (cerebral cortex, hippocampus, and cerebellum). To accomplish these objectives, three groups of rats (n=6-13/group), sedentary (SD), acute exercise (AE) and chronic exercise (ET) (5-7 weeks), ran at an intensity equal to 75% VO2max or served as controls. Gastrocnemius skeletal muscle and cerebral cortex, hippocampus, and cerebellum brain regions were analyzed using multiple methods to examine markers of OS, antioxidant factors and NrF2 protein concentration. AE significantly increased MDA concentration in the blood (~69%) and the hippocampus brain region (~36%). However, the OS response did not reflect a significant increase in NrF2 protein concentration with AE in the brain or skeletal muscle. In fact, NrF2 was significantly reduced in all brain regions and muscle with AE compared to SD. ET significantly increased GSH (~27%) and TGSH (~26%) in the hippocampus brain regions, which was concomitant with a significant increase in NrF2 protein concentration in the hippocampus with ET. In contrast, GSH, TGSH, and Mn-SOD (~44%) were significantly reduced in the in gastrocnemius skeletal muscle with ET. There were no significant differences in antioxidant factors in the cortex or cerebellum brain regions, which coincided with the lack of significant elevation in NrF2 with training. In summary, these data suggest that ET for 5-7 weeks at 75% VO2max was sufficient to increase NrF2 protein concentration and antioxidant factors in the hippocampus, a brain region that is highly susceptible to neurodegeneration. However, the single bout of acute aerobic exercise appears to be inadequate to sufficiently stress the brain and skeletal muscle tissue to increase markers of OS or NrF2 protein concentration