Resveratrol attenuated high intensity exercise training-induced inflammation and ferroptosis via Nrf2/FTH1/GPX4 pathway in intestine of mice

Abstract

Background: Moderate exercise has beneficial effects for human health and is helpful for the protection against several diseases. However, high intensity exercise training caused gastrointestinal syndrome. Resveratrol, a plant extract, plays a vital role in protecting various organs. However, whether resveratrol protected mice against high intensity exercise training-induced intestinal damage remains unclear. In this study, our objective was to investigate the protective effects and mechanism of resveratrol in high intensity exercise training-treated mice.

Methods: Mice were treated with swimming exercise protocol and/or resveratrol (15 mg/kg/day) for 28 consecutive days. Then, the mice were sacrificed, and a series of evaluation indicators, including inflammatory factors and intestinal permeability of the gut, were measured based on this model. The expressions of inflammatory factors (tumor necrosis factor (TNF)-α; interferon (IFN)-γ, interleukin (IL)-6 and IL-10), oxidative stress (Nrf2, glutathione (GSH), hydrogen peroxide (H2 O2), catalase (CAT) and malondialdehyde(MDA)), intestinal barrier (gut permeability, ZO-1, Occludin and Claudin-1 as well as ferroptosis (Fe2+, Fe3+, SLC7A11, glutathioneperoxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1)) were measured, respectively.

Results: High intensity exercise training induced colon damage, manifested as inflammation (increased TNF-α, IFN-γ and IL-6 concentrations, and decreased IL-10 concentration), oxidative stress (the increase of H2O2 and MDA concentration, and the reduced CAT and GSH activities), intestinal barrier injury (increased gut permeability and intestinal fatty-acid binding protein concentration,and inhibited ZO-1, Occludin and Claudin-1 expressions) and ferroptosis (the increased of Fe2+ and Fe3+ concentrations, and suppressed phosphorylated Nrf2, SLC7A11, GPX4 and FTH1), which was relieved by resveratrol treatment in mice.

Discussion: Resveratrol attenuated high intensity exercise training-induced inflammation and ferroptosis through activating Nrf2/ FTH1/GPX4 pathway in mouse colon, which providing new ideas for the prevention and treatment of occupational disease in athlete.

Keywords: Nrf2/FTH1/GPX4 pathway; Resveratrol; ferroptosis; high intensity exercise training; inflammation.

Figure 1

Protective effects of RES on EE-induced IFN-γ, IL-6, IL10 and TNF-α release in mice. Data represent means ± SD of 3 independent experiments with similar results. NE: nonexercise group, EE: high intensity exercise training, RES: resveratrol group, RES+EE: resveratrol+high intensity exercise training. * p < 0.05, ** p < 0.01

Figure 2

The effects of RES on intestinal permeability and IFABP concentrations in EE-treated mice. Data represent means ± SD of 3 independent experiments with similar results. NE: nonexercise group, EE: high intensity exercise training, RES: resveratrol group, RES+EE: resveratrol+high intensity exercise training. * p < 0.05, ** p < 0.01.

Figure 3

The effects of RES on ZO-1, Occludin and Claudin-1 mRNA expressions in EE-treated mice. Data represent means ± SD of 3 independent experiments with similar results. NE: nonexercise group, EE: high intensity exercise training, RES: resveratrol group, RES+EE: resveratrol+high intensity exercise training. * p < 0.05, ** p < 0.01.

Figure 4

The effects of RES on Fe²⁺, Fe³⁺, GSH, H₂O₂ and MDA concentrations, and CAT activities in EE-treated mice. Data represent means ± SD of 3 independent experiments with similar results. NE: nonexercise group, EE: high intensity exercise training, RES: resveratrol group, RES+EE: resveratrol+high intensity exercise training. ** p < 0.01.

Figure 5

The effects of RES on ferroptosis through Nrf2/GPX4 pathway in EE-treated mice. Data represent means ± SD of 3 independent experiments with similar results. NE: nonexercise group, EE: high intensity exercise training, RES: resveratrol group, RES+EE: resveratrol+high intensity exercise training. * p < 0.05, ** p < 0.01.

Figure 6

Resveratrol attenuated high intensity exercise training-induced and inflammation through Nrf2/FTH1/GPX4 pathway-regulated ferroptosis in mice. Green arrow and red bar indicate stimulation and inhibition, respectively.