Abstract 175: Doxorubicin and Acute Exercise Training Impair Diastolic Before Systolic Function in a Murine Model of Cancer

Abstract

Introduction: Cardiotoxicity often occurs in cancer patients treated with doxorubicin (DOX). DOX induces cardiomyocyte death, due in part to DOX-mediated DNA damage, myofiber degeneration, ischemia-related metabolic alterations, and activation of apoptotic pathways. While exercise is often recommended for cancer patients, it remains unclear whether the metabolic stress of exercise with DOX treatment benefits or impairs cardiac performance. Purpose: To test the hypothesis that acute exercise training performed with DOX therapy offsets cardiotoxicity. Methods: B16F10 melanoma cells (3x10 5 ) were injected into 6-8 week old male C57BL/6 mice (n= 48). A 4 mg/kg cumulative dose of DOX (IP) was administered over 2 weeks and exercise (EX) consisted of treadmill walking (45 min/d, 10 m/min, 5 days/week, 2 weeks). Four groups were tested: 1) Sedentary (SED) +Vehicle, 2) SED +DOX, 3) EX+Vehicle, 4) EX+DOX. Echocardiography [LV systolic (EF, %) and diastolic (E/A ratio) function] and tissue harvest were performed 48 hours after EX. Results: Tumor volume was attenuated in DOX and lowest in EX+DOX (p<0.05). Body weight (BW), heart weight (HT), HT/BW, and HT/Tibia were attenuated in DOX (p<0.05) and were lowest in EX+DOX. LV fibrosis increased with DOX (p<0.05) and was greatest in EX+DOX (SED+Vehicle 2 ± 0.3%, SED+DOX 4 ± 0.5%, EX+Vehicle 3 ± 0.3%, and EX+DOX 6 ± 0.4%; p<0.05). Cardiomyocyte area and β myosin heavy chain gene expression were similar between groups. Diastolic function was reduced with DOX and EX+DOX (both p<0.05), but systolic function was similar between groups. DOX induced significant alterations the expression profiles of genes in the mTOR signaling pathway, with similar expression patterns in SED+DOX and EX+DOX. Insulin improved in vitro cardiomyocyte cell survival (p<0.05) to a greater extent than IGF-1 treatment during DOX. Neither insulin nor IGF-1 impacted cardiomyocyte proliferation during DOX. Conclusion: While the addition of EX to DOX treatment more effectively inhibited tumor growth, EX did not alleviate DOX mediated LV diastolic impairment, and actually increased LV fibrosis. Acute, short term exercise appears to impair LV function in DOX-treated mice. Exercise-induced reductions in insulin secretion may underlie this effect.