Effects of high-intensity aerobic exercise during multiple cycles of doxorubicin treatment on cardiac catabolism

[Purpose] Doxorubicin causes dose-dependent cardiotoxicity characterized by cardiac atrophy. Although moderate-intensity aerobic exercise may mitigate doxorubicin cardiotoxicity, the effects of high-intensity aerobic exercise during doxorubicin treatment on cardiac homeostasis remain unclear. Therefore, this study investigated the impact of high-intensity aerobic exercise (EXE) during doxorubicin (DOX) chemotherapy on cardiac autophagy, protein catabolism, and lipolysis.[Methods] Male C57BL/6J mice were randomized into sedentary-saline, exercise-saline, sedentary-doxorubicin, and exercise-doxorubicin groups. Doxorubicin was administered intraperitoneally (5 mg/kg, 5 times at 2-week intervals, totaling 25 mg/kg). The exercise groups performed high-intensity treadmill running (12-15 m/min, 60 min/day, for 7 weeks) during doxorubicin treatment. Body and heart weights were measured, and cardiac tissues were analyzed via Western blotting.[Results] Doxorubicin reduced the body and heart weights, and the combination of exercise and doxorubicin further exacerbated these effects. While exercise administered during doxorubicin treatment improved autophagic flux and enhanced lipolysis, it significantly exacerbated cardiac protein catabolism, as evidenced by decreased structural proteins (β-actin, Talin), upregulated ubiquitin-proteasome system components, and increased proteolytic cleavage in the exercise-doxorubicin group compared to the sedentary-doxorubicin group. These findings demonstrate a complex interaction between exercise during doxorubicin treatment, while simultaneously promoting the clearance of damaged components through enhanced lipid utilization and amplifying the degradation of essential cardiac structural proteins.[Conclusion] These results suggest that concurrent high-intensity aerobic exercise during cardiotoxic chemotherapy regimens may compromise myocardial integrity.