Binge alcohol induces NRF2-related antioxidant response in the skeletal muscle of female mice.

Background Chronic alcohol enhances oxidative stress, but the temporal response of antioxidant genes in skeletal muscle following a binge drinking episode remains unknown. Methods Experiment 1: C57BL/6Hsd female mice received an IP injection of saline (CON; n=39) or ethanol (ETOH; n=39) (5g/kg). Gastrocnemius muscles were collected from baseline (untreated; n=3), CON (n=3), and ETOH (n=3) mice every 4 hours for 48 hours. Experiment 2: Gastrocnemius muscles were collected from control-fed (CON-FED; n=17), control-fasted (CON-FAST; n=18), or alcohol-fed (ETOH-FED; n=18) mice every 4hrs for 20hrs after saline or ethanol (5g/kg). Results EtOH enhanced Superoxide dismutase 1 (Sod1) and NADPH Oxidase 4 (Nox4) from 24-48hr after the binge, while Sod2 and Nox2 were suppressed. Nuclear factor erythroid-derived 2-like 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) increased 12hrs after intoxication. Cytochrome P450 oxidoreductase (Por), Heme oxygenase 1 (Ho1), Peroxiredoxin 6 (Prdx6), Glutamate-cysteine ligase catalytic subunit (Gclc), Glutamate-cysteine ligase modifier subunit (Gclm), and Glutathione-disulfide reductase (Gsr) were increased by ETOH starting 12-16hrs post-binge. Fasting had similar effects on Nrf2 compared to alcohol, but downstream targets of NRF2, including Por, Ho1, Gclc, and Gclm, were differentially altered with fasting and EtOH. Conclusion These data suggest that acute alcohol intoxication induced markers of oxidative stress and antioxidant signaling through the NRF2 pathway and that there were effects of alcohol independent of a possible decrease in food intake caused by binge intoxication.