Effects of high-intensity interval training on the expression of microRNA-499 and pro- and anti-apoptotic genes in doxorubicin-cardiotoxicity in rats

Background: Because clinical use of doxorubicin (DOX) in chemotherapy is limited due to cardiotoxicity, finding new strategies to alleviate DOX burden and improving patients' health are necessary. Due to positive cardiovascular impacts of high-intensity interval training (HILT), here we have investigated the effect of HIIT on DOX-induced cardiotoxicity by evaluating the myocardial apoptosis mechanism as well as microRNA-499a-5p expression. Methods: Male Wistar rats (250-270 g) were randomly allocated into four groups: control, HILT, DOX, and HIIT +DOX. HIIT was performed as 7 sets of alternative intervals of high and low trainings for 1 h a day, 5 days a week for 6 weeks using a rodent treadmill. After the last session of HIIT, the trained and time-matched control rats received intraperitoneal injection of DOX (20 mg/kg). Three days later, the left ventricular samples were obtained to determine the expression of microRNA and genes and proteins regulating apoptosis via real-time PCR. Myocardial apoptosis was also evaluated using TUNEL staining method. Results: DOX administration significantly increased the expression levels of Bax and caspase-6 mRNA5, Bax protein and Bax/Bcl2 ratio, while reduced the expression levels of Bcl2 mRNA and protein in comparison to control group (P < 0.01). Pre-treatment of DOX-received rats with HIIT significantly up-regulated the Bcl2 and reduced the Bax, Bax/Bcl2, and caspase-6 expression profiles toward control values (P < 0.05), not affecting GSK-3 beta expression. In addition, DOX toxicity significantly overexpressed microRNA-499, comparing to control rats (P < 0.01). HIIT significantly reversed this overexpression and also reduced TUNEL-positive apoptotic cells in DOX-received rats (P < 0.05). Conclusions: The data suggested that prior training of rats with MIT had protective effect on DOX cardiotoxicity through reversing the expression profiles of pro- and anti-apoptotic factors and microRNA-499 and reducing myocardial apoptosis. (C) 2019 Published by Elsevier Inc.