The Role of Mitochondrial ABCB8 in Exercise-Induced Protection Against DOX Cardiotoxicity

Abstract

Doxorubicin (DOX) is a highly effective chemotherapeutic used in cancer treatment. However, its use is associated with the development of cardiac dysfunction, which can negatively affect patient outcomes and reduce overall survival. While no clinical countermeasure exists to combat DOX cardiotoxicity, endurance exercise preconditioning is sufficient to preserve cardiac function following acute DOX exposure. In this regard, it is established that DOX cardiotoxicity is associated with increased mitochondrial reactive oxygen species (ROS) production and iron accumulation and that endurance exercise training stimulates an increase in the expression of the mitochondria-localized ATP-binding cassette subfamily B member 8 (ABCB8) transporter. Overexpression of ABCB8 has been shown to prevent DOX cardiac dysfunction. Therefore, we tested the hypothesis that increased levels of ABCB8 are required for exercise-induced cardioprotection against DOX toxicity. Cause and effect were determined by preventing the exercise-induced increase in ABCB8 expression using an antisense oligonucleotide (AO) designed to specifically target ABCB8. Young adult female Sprague-Dawley rats remained sedentary (SED) or were treadmill exercise trained (EX) for 2 weeks (70% VO2MAX, 1hr/day, 10 days). Immediately following each exercise bout or at identical time points, rats received either AO (10mg/kg i.p.) or saline. Rats then received either a bolus dose of DOX (20mg/kg i.p.) or saline (SAL) treatment 24 hours after the last exercise bout. Dependent measures were evaluated 48 hours after DOX or saline administration. Body weight change following DOX/SAL treatment showed significant weight loss in all DOX-treated groups, with the greatest weight change occurring in the EX-AO-DOX rats. Additionally, EX-AO-DOX treatment prevented the rescue of heart weight/tibia length seen in the EX-DOX group. Exercise capacity was assessed via a graded exercise tolerance test and revealed a significant reduction in running time in both the SED-DOX and EX-AO-DOX groups compared to SED-SAL. Interestingly, mitochondrial ROS emission was not elevated in the EX-AO-DOX treatment group compared to SED-SAL. Collectively, these results reveal that exercise-induced ABCB8 expression contributes to the protective effect of exercise against DOX cardiotoxicity. NIH R01 HL146443, NIH R01 HL144858, T32 HD043730 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.