Effects Of Exercise Preconditioning Against Doxorubicin Cardiotoxicity Are Affected By Exercise Modality And Doxorubicin Dose

Abstract

Previous studies have shown long-term and short-term exercise preconditioning protects against doxorubicin (DOX) cardiotoxicity. However, it is unclear to what extent exercise modality and DOX dosage may influence exercise-induced cardioprotection. PURPOSE: To determine whether the positive effects of short-term exercise preconditioning against DOX-induced cardiotoxicity are affected by exercise modality and DOX dose. METHODS: Male Sprague-Dawley rats were randomly assigned to sedentary (SED), wheel-run (WR), or treadmill-run (TM) groups. Animals in WR and TM participated in 5 days of either treadmill training or voluntary wheel-running. SED animals remained in their cages duration the 5 day period. After 5 days, animals were randomly assigned to receive 10 mg/kg DOX (SED + DOX10, WR + DOX10, TM + DOX10), 15 mg/kg DOX (SED + DOX15, WR + DOX15, TM + DOX15) or saline (SED + SAL, WR + SAL, TM + SAL). Following the exercise/sedentary period all animals then remained sedentary for 5 days after DOX/SAL treatments. Ex vivo left ventricular function was measured using an isolated working heart model. RESULTS: SED + DOX10, SED + DOX15, and TM + DOX15 had significantly lower left ventricular developed pressure (LVDP) (34%, 39% and 19%, respectively, P < 0.05). However, LVDP of TM + DOX10, WR + DOX10 and WR + DOX15 were not significantly different than SED + SAL (P > 0.05). In addition, maximal rate of left ventricular pressure development (+dP/dt) in SED + DOX10, SED + DOX15 and TM + DOX15 were significantly lower than SED + SAL (P < 0.05). This reduction in + dP/dt, however, was not observed in the TM + DOX10, WR + DOX10 and WR + DOX15. CONCLUSION: Short-term treadmill or voluntary wheel running attenuated DOX-induced early onset cardiac dysfunction in animals treated with 10mg/kg DOX. In contrast, only short-term voluntary wheel running protected against DOX-induced early onset cardiac dysfunction in animals treated with 15 mg/kg DOX. These data suggest that while both treadmill and voluntary wheel running can protect against DOX cardiotoxicity, wheel running appears to afford enhanced protection against at higher doses.