The Effects Of High-intensity Endurance Exercise Between Multiple Doxorubicin Treatment Cycles On Cardiac Catabolism.

PURPOSE: Doxorubicin (DOX) is a highly effective chemotherapeutic agent, but cardiotoxic side effects limit its clinical use. Exercise preconditioning (exercise before DOX therapy) or postconditioning (exercise after DOX therapy) has been reported to mitigate DOX-induced cardiotoxicity. However, it remains unknown whether exercise administration between multiple cycles of DOX therapy confers the same or better auspicious outcomes or should be avoided due to potential adverse effects on DOX-induced cardiotoxicity. Therefore, the present study explored the effects of long-term high-intensity exercise administered between 5 cycles of DOX treatment on cardiotoxicity. METHODS: Twelve-week-old male C57BL/6 J mice were assigned to four groups: Control group (CON, n = 7), Control-Exercise group (CE, n = 7), Doxorubicin group (DOX, n = 7), Doxorubicin-Exercise group (DE, n = 7). DOX (5 mg/kg) was intraperitoneally injected five times biweekly for 8 weeks during which 7 weeks of treadmill exercise (15 m/min, 60 min/day, 5 days/week) were employed. Body and heart weights were assessed, and then heart tissues were homogenized for western blot. RESULTS: DOX and DE groups exhibited a significant loss in body and heart weight compared to other groups; intriguingly, the extent of those losses was greater in the DE group than in the DOX group. In line with those losses, DOX and DE groups displayed increases in catabolic processes, including basal autophagy (elevations in LC3-II, p-AMPK, p-ULK1, BNIP3, ATG7, LAMP2, and Cathepsin L). Subsequently, autophagy flux (a reduction in p62 alongside LC3-II elevation) was greater in the DE than in the DOX group; moreover, a crucial muscle atrophy marker (e.g., MuRF1) was upregulated only in the DE group although oxidative stress markers (e.g., 4HNE) were equally increased in both DOX and DE groups. CONCLUSIONS: Prolonged high-intensity endurance exercise employed between multiple cycles of DOX worsened DOX-induced catabolic processes by enhancing autophagy flex and atrophy signaling. Our findings suggest that high-intensity endurance exercise during DOX chemotherapy may negatively affect heart health and thus should be avoided. However, further research is needed on therapeutic approaches to exercise before or after DOX treatment to prevent DOX-induced loss of heart muscle.