Mechanism by which hydrogen-rich water mitigates exercise-induced fatigue: activation of the immunoresponsive gene 1-itaconate/nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway

Abstract

Exercise-induced fatigue limits athletic performance. Molecular hydrogen is an effective treatment for relieving fatigue, but the exact mechanism is not clear. In our study, a mouse model of fatigue was established to explore the molecular mechanism by which hydrogen-rich water reduces exercise-induced fatigue. The results showed that hydrogen-rich water improved the motor function of fatigue mice, reduced the levels of fatigue-related biomarkers (blood urea nitrogen, lactate, and creatine kinase), and alleviated gastrocnemius muscle injury. Furthermore, ultrahigh-performance liquid chromatography‒mass spectrometry revealed that hydrogen-rich water upregulated the expression of immune response gene 1 (IRG1), increased the abnormally reduced levels of itaconic acid due to fatigue, and subsequently activated the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. Finally, C2C12 cells exposed to an IRG1 inhibitor (IRG1-IN) or 4-octyl itaconic acid (4-OI) were treated with hydrogen-rich water, indicating that hydrogen-rich water effectively upregulated the expression of Nrf2 and HO-1 in cells. In summary, hydrogen-rich water alleviates exercise-induced fatigue by activating the IRG1-itaconic acid/ Nrf2/HO-1 pathway and inhibiting oxidative stress.

Study details

Article type

Original Research

Disease / injury model

Exercise-induced fatigue

Duration

4 weeks

Dose-dependent effect

No

Outcome

Positive

Findings

Hydrogen-rich water alleviates exercise-induced fatigue in mice by improving motor function, reducing fatigue-related biomarkers (blood urea nitrogen, lactate, creatine kinase), and alleviating muscle injury. Mechanistically, it upregulates IRG1, restores itaconate levels, and activates the Nrf2/HO-1 pathway, thereby reducing oxidative stress.