High-intensity interval training enhanced cardioprotective effects of neuregulin-1 against doxorubicin-induced cardiotoxicity

Doxorubicin (DOX) is an anthracycline chemotherapeutic agent widely used to treat a various cancer due to its potent therapeutic effects. However, its clinical application is limited by severe toxicity in multiple tissues particularly the heart, as well as liver, kidneys, and nervous system. Neuregulin-1 (NRG-1), an epidermal growth factor produced by cardiac endothelial cells, plays a protective role against these injuries by activating ErbB2/4 receptors and the PI3K/Akt signaling pathway. Evidence suggests that NRG-1 prevents myofibrillar damage and troponin degradation. In addition, exercise as a non-pharmacological intervention enhances these protective pathways by upregulation NRG-1 signaling and reducing cardiomyocytes apoptosis induced by DOX. The aim of this study was to investigate the effects of eight weeks of high-intensity interval training (HIIT) on NRG-1/ErbB signaling pathway in male Wistar rats induced by DOX-induced cardiotoxicity. Twenty-four male Wistar rats were randomly assigned into three groups ( n = 8 per group): control healthy, DOX control, and DOX-HIIT. Cardiotoxicity was induced by six intraperitoneal injections of DOX (2 mg/kg per dose) administrated over a 12-day period, while the healthy control group received normal saline. The exercise protocol consisted of eight weeks of HIIT, performed three times per week. Each session included a 5-min warm-up, five 4-min high-intensity interval (85–90% of maximum oxygen consumption [VO 2 max]) interspersed with 2-min active recovery (50–60% of VO 2 max), and a 5-min cool-down. The end of the intervention, cardiac tissue and blood samples were collected for analysis. Protein expression was assessed using Western blotting. Statistical analysis was performed using one-way ANOVA followed by Tukey’s post hoc test. The results demonstrated that HIIT significantly improvements in left ventricular end-systolic diameter, stroke volume, ejection fraction, and fractional shortening compared to DOX-treated sedentary rats. These findings indicated that HIIT attenuates DOX-induced structural and functional cardiac impairment, potentially through modulation of the NRG-1/ErbB signaling pathway.