First Advisor

Hayward, Reid

Document Type

Dissertation

Date Created

8-1-2011

Department

College of Natural and Health Sciences, Kinesiology Nutrition and Dietetics, KiND Student Work

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic that has cytotoxic actions. The therapeutic use of DOX to treat a wide array of cancers is limited by a dose-dependent cardiotoxicity. Although DOX is known to have several adverse side-effects, acute and chronic cardiotoxicity have received the most attention as both may eventually lead to heart failure. While exercise has been shown to protect against DOX cardiotoxicity, a clear and consistent mechanism to explain its cardioprotective effects is lacking. High performance liquid chromatography (HPLC) is a valuable instrument that can be used to evaluate cardiac DOX accumulation. We hypothesized that a reduction in cardiac DOX accumulation may be a mechanism of exercise-induced cardioprotection. Therefore, the purpose of this study was to determine if exercise preconditioning reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity. Female Sprague-Dawley rats were randomly assigned to 1 of 3 primary experimental groups: sedentary (SED), voluntary wheel running (WR) or treadmill (TM). Animals in WR and TM groups completed 10 weeks of exercise prior to DOX treatment. DOX was administered 24 hours after the last training session as a bolus i.p. injection at 10 mg/kg. Subgroups of rats from each primary group were sacrificed at 1, 3, 5, 7, and 9 days post exposure and cardiac function was analyzed. Twenty-four hours following sacrifice, cardiac DOX accumulation was analyzed using HPLC. DOX treatment resulted in both in vivo and ex vivo cardiac dysfunction. However, 10 weeks of either involuntary or voluntary exercise preconditioning preserved cardiac function. Additionally, significant differences were observed between sedentary and exercise groups for DOX accumulation. The greatest accumulation of DOX was observed in SED+DOX 1 day post injection. When compared to SED+DOX (day 1), DOX accumulation in TM+DOX (day 1) and WR+DOX (day 1) groups was significantly reduced (p < 0.05). Similarly, DOX accumulation in SED+DOX at both 3 and 5 days was significantly greater than both TM+DOX and WR+DOX at 3 and 5 days, respectively (p < 0.05). DOX accumulation in TM+DOX and WR+DOX groups was non-existent at both 7 and 9 days. Because DOX accumulation remained elevated in SED+DOX at 7 days, it was significantly greater than TM+DOX and WR+DOX groups (p < 0.05). Therefore, it is possible that the cardioprotective effects of exercise against acute DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.

Abstract Format

html

Keywords

Exercise; Cardioprotection; Cardiotoxicity; Doxorubicin

Extent

138 pages

Local Identifiers

Jensen_unco_0161D_10078.pdf

Rights Statement

Copyright is held by author.

Digital Origin

Born digital

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