Trilobatin, a Naturally Occurring Food Additive, Ameliorates Exhaustive Exercise-Induced Fatigue in Mice: Involvement of Nrf2/ARE/Ferroptosis Signaling Pathway

Abstract

Nrf2-mediated oxidative stress is a promising target of exhaustive exercise-induced fatigue (EEIF). Trilobatin (TLB) is a naturally occurring food additive with antioxidant effect and Nrf2 activation potency. The present study aimed to investigate the effect of TLB on EEIF and elucidate its underlying mechanism. Our results showed that TLB exerted potent anti-EEIF effect, as reflected by the rope climbing test and exhaustive swimming test. Moreover, TLB also effectively reduced the levels of lactate, creatine kinase, and blood urea nitrogen, and increased liver glycogen and skeletal muscle glycogen in mice after EEIF insult. Additionally, TLB also balanced the redox status as evidenced by decreasing the generation of reactive oxygen species and improving the antioxidant enzyme activities including superoxide dismutase, catalase, and glutathione peroxidase, as well as the level of glutathione both in the tissue of muscle and myocardium. Furthermore, TLB promoted nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, and upregulated its downstream antioxidant response element (ARE) including quinone oxidoreductase-1 and heme oxygenase-1. Intriguingly, TLB also upregulated the GPx4 protein expression and reduced iron overload in mice after EEIF insult. Encouragingly, the beneficial effect of TLB on EEIF-induced oxidative stress and ferroptosis were substantially abolished in Nrf2-deficient mice. In conclusion, our findings demonstrate, for the first time, that TLB alleviates EEIF-induced oxidative stress through mediating Nrf2/ARE/ferroptosis axis.

Ferroptosis and its role in skeletal muscle diseases

“…Frontiers in Molecular Biosciences frontiersin.org Braake et al, 2008;Sikalidis et al, 2014;Sun et al, 2018;Xu Y. et al, 2022). In addition to the above-mentioned cysteine, glutamate is another essential amino acid for GSH synthesis, and glutaminolysis is one of its sources (Whillier et al, 2011).…”

“…Another study showed that the ferroptosis-related gene CISD1 is anticipated to become one of the novel biomarkers for predicting the prognosis of breast cancer patients, thereby providing a new target for cancer therapy (Wang D. et al, 2021) (Figure 2). such as sarcopenia, RML, RMS, and EEIF (Guerrero-Hue et al, 2019;Dachert et al, 2020;Huang et al, 2021;Xiao et al, 2022). Therefore, we summarized the functions of ferroptosis in the pathogenesis of these skeletal muscle diseases.…”

“…RML is an acute clinical syndrome caused by the injury of skeletal muscle cells and the release of intracellular components (such as myoglobin and creatine kinase) into the systemic circulation (Lindner and Zierz, 2003;Stahl et al, 2020). It is exhibited in study that ferroptosis of skeletal muscle cells induced by the inhibition of the antioxidant axis Nrf2-XCT/GPX4 is one of the potential mechanisms of atorvastatin-induced muscle-related symptoms (muscle weakness, pain, cramps, and RML) (Zhang Q. et al, 2022). It suggests that ferroptosis may be related to the disease progression of RML.…”

“…Therefore, ferroptosis may be a new type of cell death that participates in the physiological and pathological process of EEIF except apoptosis (Sun Y. et al, 2016;Liu S. et al, 2022). Excitingly, a recent report explored the relationship between ferroptosis and EEIF (Xiao et al, 2022). The experimental data showed that there were characteristics related to ferroptosis in skeletal muscle of EEIF mice, such as accumulation of iron, lipid peroxide, decreased expression of GPX4 and GSH, suggesting that ferroptosis may participate in the process of EEIF disease (Xiao et al, 2022).…”

“…Recent studies have found that ferroptosis is an important RCD that induces skeletal muscle cell death and prevents skeletal muscle proliferation and differentiation (Guerrero-Hue et al, 2019;Ding et al, 2021;Huang et al, 2021). At the same time, ferroptosis is repeatedly reported to be associated with skeletal muscle disease processes such as sarcopenia, RML, RMS, and EEIF (Guerrero-Hue et al, 2019;Dachert et al, 2020;Huang et al, 2021;Xiao et al, 2022). The exact role of ferroptosis in these diseases, however, has not been systematically elucidated.…”