Mechanism by which hydrogen-rich water mitigates exercise-induced fatigue: activation of the immunoresponsive gene 1-itaconate/nuclear factor . . .

[Mij]

Full Title: 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, 2026, Zhang, Yinyin et al

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.
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[Mij]

Hydrogen-rich water alleviated fatigue by increasing itaconate​

Considering the vital role of metabolites in bridging aberrant energy metabolism, we used UPLC/Q-TOF-MS to characterize the metabolic variations in the serum samples among the three groups. We detected 31 aberrant metabolic variations in our serum samples, including purine metabolism, cytosine metabolism, glucose metabolism, amino acid metabolism, fatty acid metabolism, and phospholipid metabolism pathways

The UPLC/Q-TOF-MS analytical procedure incorporated rigorous quality control measures to ensure data reliability and metabolic variations were shown as a heatmap

Hydrogen-rich water treatment could reverse the above metabolic disorders, especially itaconate. Itaconate is synthesized by the decarboxylation of cis-aconitate, an intermediate product of the TCA cycle, which is catalyzed by immune-responsive gene 1 protein (IRG1). We further detected the expression of IRG1 in the gastrocnemius

These results implied that hydrogen-rich water upregulates the expression of IRG1 to restore the decarboxylation of cis-aconite acid and increases itaconate, which aberrantly decreases in response to fatigue.

 

[Mij]

Our results highlight the protective effects of hydrogen-rich water on exercise-induced fatigue through the upregulation of IRG1 to rescue itaconate and activate downstream Nrf2/HO-1 to alleviate oxidative stress damage. The convenience, inexpensiveness, and low toxicity enable hydrogen-rich water a promising measure to improve locomotion performance and damage. Itaconate, a glycolysis product, may serve as a novel intermediate molecule bridging glycolysis and oxidative stress and function as a new H2 treatment target.