Aerobic exercise modulates cardiac NAD(P)H oxidase and the NRF2/KEAP1 pathway in a mouse model of chronic fructose consumption

Abstract

The present study investigated the effects of exercise on the cardiac nuclear factor (erythroid-derived 2) factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) pathway in an experimental model of chronic fructose consumption. Male C57BL/6 mice were assigned to Control, Fructose (20% fructose in drinking water), Exercise (treadmill exercise at moderate intensity), and Fructose + Exercise groups ( n = 10). After 12 wk, the energy intake and body weight in the groups were similar. Maximum exercise testing, resting energy expenditure, resting oxygen consumption, and carbon dioxide production increased in the exercise groups (Exercise and Fructose + Exercise vs. Control and Fructose groups, P < 0.05). Chronic fructose intake induced circulating hypercholesterolemia, hypertriglyceridemia, and hyperleptinemia and increased white adipose tissue depots, with no changes in blood pressure. This metabolic environment increased circulating IL-6, IL-1β, IL-10, cardiac hypertrophy, and cardiac NF-κB-p65 and TNF-α expression, which were reduced by exercise ( P < 0.05). Cardiac ANG II type 1 receptor and NAD(P)H oxidase 2 (NOX2) were increased by fructose intake and exercise decreased this response ( P < 0.05). Exercise increased the cardiac expression of the NRF2-to-KEAP1 ratio and phase II antioxidants in fructose-fed mice ( P < 0.05). NOX4, glutathione reductase, and catalase protein expression were similar between the groups. These findings suggest that exercise confers modulatory cardiac effects, improving antioxidant defenses through the NRF2/KEAP1 pathway and decreasing oxidative stress, representing a potential nonpharmacological approach to protect against fructose-induced cardiometabolic diseases. NEW & NOTEWORTHY This is the first study to evaluate the cardiac modulation of NAD(P)H oxidase (NOX), the NRF2/Kelch-like ECH-associated protein 1 pathway (KEAP), and the thioredoxin (TRX1) system through exercise in the presence of moderate fructose intake. We demonstrated a novel mechanism by which exercise improves cardiac antioxidant defenses in an experimental model of chronic fructose intake, which involves NRF2-to-KEAP1 ratio modulation, enhancing the local phase II antioxidants hemoxygenase-1, thioredoxin reductase (TXNRD1), and peroxiredoxin1B (PDRX1), and inhibiting cardiac NOX2 overexpression.

Beneficial Effects of High Intensity Interval Training and/or Linseed Oil Supplementation to Limit Obesity-Induced Oxidative Stress in High Fat Diet-Fed Rats

“…Here again, to our knowledge, we are the first to show a positive effect of HIIT on NOx in liver in a model of obesity. Our result is consistent with Alves et al [67] who reported that cardiac NOx expression is increased in fructose diet-fed mice and that HIIT decreases this response.…”

The Impact of Resistance Training With Coenzyme Q10 Supplementation on Antioxidant Value of Nuclear Factor-Erythroid-2-Related Factor 2 in Young Male Rats

“…In our study, Q10 supplementation elevated Nrf2 and NQO1 levels more significantly in the exercise and supplementation groups than in the control group. In a previous report in Q10 hepatocytes, inhibiting hepatic fibrosis through ARE-Nrf2 activation, the researchers speculated that Q10interceded Nrf2 activation can lead to stable self-acting oxidation of the quinone portion (33). Thus, our findings support the notion that weight training can increase Nrf2, which is more evident in Q10 resistance training and supplementation rats.…”

Mango ginger (Curcuma amada Roxb.) may alleviate the effect of high‐fat diet/streptozotocin‐induced diabetes by activation of the GSK‐3β/Fyn/Nrf2 pathway

“…Fyn promotes the nuclear export of Nrf2, leading to its degradation (Yi et al, 2018 ). Increasing the ratio of Nrf2 to Keap1 may enhance the Nrf2/Keap1 signaling activity and prevent Nrf2 degradation (Alves et al, 2019 ; Zhang et al, 2020 ). Moreover, GSK‐3β may suppress the Nrf2/HO‐1 pathway in diabetic rats and negatively affects antioxidant signaling (Shen et al, 2017 ).…”