Abstract 10138: Exercise Inhibits Doxorubicin-Induced Cardiotoxicity by Preventing Cardiomyocyte Cellular Senescence

Abstract

Introduction: Doxorubicin (Dox) induces cardiomyocyte cellular senescence thru proinflammatory mechanisms and by damaging DNA, resulting in Dox-induced cardiotoxicity. Inhibiting cardiomyocyte cellular senescence inhibits Dox-induced cardiac damage. We showed that exercise inhibits both acute and late Dox-induced cardiotoxicity using our juvenile cardiotoxicity mouse model. Here we used p16-3MR transgenic mice to track the induction of senescent cardiomyocytes to determine whether exercise prevents Dox-induced cardiotoxicity by inhibiting senescence. Hypothesis: Cellular senescence plays a key role in Dox-induced cardiotoxicity in the heart following therapy. Exercise prevents Dox-induced cardiotoxicity by inhibiting myocardial cell senescence. Methods: To confirm induction of senescence by Dox in vitro , mouse cardiomyocytes were isolated and treated with 250 nmol/L Dox for 24 h for 24h cells, washed and then analyzed 7 days later for senescent markers. Mice were treated with PBS, Dox (2.5mg/kg 2x/wk for 2 wks), or Dox + exercise (walking 45 min/day at 12 meter/min). Cardiac function was evaluated by echocardiography 24 h after therapy to confirm Dox-induced cardiotoxicity. Heart tissue was collected 14 days after therapy. Tissue sections were analyzed by immunohistochemical and Western immunoblot. Results: Dox-induced senescence was confirmed by a significant increase in β-galactosidase in cardiomyocytes from the in vitro study. Decreased ejection fraction, fractional shortening and F-actin distribution was seen in Dox but not Dox + exercise-treated mice confirming Dox-induced cardiotoxicity and prevention of heart damage by exercise. There was an increase in p16 INK4a expression (signifying senescent cells) in cardiac tissue from Dox-treated but not Dox + exercise-treated mice compared with PBS controls. Conclusion: Taken together our data demonstrated that exercise inhibited Dox-induced cardiotoxicity by inhibiting the induction of cardiomyocyte senescence.