Swimming Exercise Attenuates Dox-Induced Cardiotoxicity by Modulating Apoptosis and DRP1/PGC1α/ miR-23a Dependent Pathway in Rat Heart Tissue

Background: Doxorubicin (DOX) is a widely used drug in cancer chemotherapy, but its cardiotoxicity limits its clinical applications. Combining exercise with chemotherapy offers a promising approach to mitigate the side effects of chemotherapy drugs. Limited information is available on the effects of swimming exercise on the molecular mechanisms related to Dox cardiotoxicity. This study aims to investigate the modulatory effect of swimming exercise on the apoptosis and miR-23a-dependent mitochondrial biogenesis and dynamics pathways in rat heart tissue treated with dox. Methods: In this experimental study, thirty-two adult male Wistar desert rats (200-220 g) were randomly divided into four groups, including control, doxorubicin (DOX; intraperitoneal injection of 5 mg/kg of Dox, once a week, for five weeks), swimming exercise (SE; water exercise for 60 min/day, five days a week, for six weeks) and Dox group along with Swimming Exercise (DOX-SE). At the end of the study, the cardiac expression of proteins related to apoptosis and mitochondrial biogenesis and mir23-a were analyzed using western blot and real-time PCR methods, respectively. One-way analysis of variance (ANOVA)with Tukey's post hoc test was used to analyze the data. Results: These findings revealed that DOX administration led to a significant decrease in the cardiac expression of PGC-1α and DRP-1 proteins and an increase in apoptotic proteins (caspase 3 and cytochrome C) compared to the control group (p<0.0001). Swimming exercise resulted in a significant increase expression in cardiac tissue of PGC-1α and DRP-1 proteins and a decrease in the expression of apoptotic proteins in the DOX-treated group (p<0.0001, p<0.01). Compared to the control group, the protein levels in the heart of the miR-23a were significantly increased in the DOX-treated group (p<0.001). However, exercise training attenuated the DOX-induced reduction in miR-23a expression gene in the cardiac muscle of DOX-treated mice (p<0.05). Conclusion: These findings suggest that swimming exercise may protect against DOX-induced cardiotoxicity by regulating apoptosis and DRP1/PGC1α/ miR-23a pathway. This highlights exercise as a potential non-pharmacological strategy to mitigate chemotherapy-related heart damage.