Exercise Rehabilitation Preserves Cardiorespiratory Muscle Function Following Doxorubicin Treatment

Doxorubicin (DOX) is a highly effective chemotherapeutic agent. Unfortunately, cancer patients who have completed DOX treatment often experience exercise intolerance, reduced cardiac function, dyspnea and unfavorable changes to body composition, ultimately, leading to increased incidence of heart failure. Exercise has been shown to reduce the risk of developing chemotherapy-induced cardiorespiratory dysfunction; however, the ability of cancer patients to exercise during treatment can be limited by cancer type, stage and fatigue. Therefore, these experiments utilized a chronic DOX-induced cardiotoxicity model to determine the effects of rehabilitative exercise on cardiorespiratory muscle function. Female Sprague-Dawley rats were treated with DOX once every three weeks for four total cycles via intravenous infusion (i.e., cumulative dose of ~160mg/m 2 ). One-week following the completion of DOX treatment, rats remained sedentary (Sed-DOX) or were prescribed 10-weeks of moderate intensity treadmill running at 30m/min, 0% grade, 1-hour/day, and 3x/week (Mod-DOX). Body composition, exercise tolerance and echocardiography were assessed at three timepoints: 1) pre-treatment; 2) post-treatment and; 3) post-rehabilitation. Diaphragm muscle specific force production was measured post-rehabilitation. From pre- to post-treatment each group gained weight and no differences existed between groups. However, from post-treatment to post-rehabilitation body weight of the DOX-treated groups did not change and was significantly reduced compared to sedentary saline-treated (Sed-Sal) rats from week 15 onwards. Although mean body weight did not differ between the DOX-treated groups, lean mass increased in Mod-DOX rats between each timepoint with no change in fat mass, while fat mass increased in Sed-DOX rats and an initial increase in lean mass was attenuated from post-treatment to post-rehabilitation. Exercise time to fatigue did not change between timepoints within each group; however, exercise run time from post-treatment to post-rehabilitation was significantly longer in Mod-DOX rats compared to Sed-DOX and Sed-Sal. Cardiac fractional shortening percentage (FS%) was reduced in Sed-DOX rats at post-treatment and post-rehabilitation compared to pre-treatment. Additionally, posterior wall shortening velocity (PWSV) was reduced in Sed-DOX rats at post-treatment compared to pre-treatment. No differences in FS% or PWSV were seen between any timepoint in the Mod-DOX group. Finally, ex vivo diaphragm muscle function showed significant diaphragm muscle weakness in Sed-DOX rats at 15-60Hz stimulations compared to Sed-Sal. Diaphragm force production did not differ in Mod-DOX rats compared to Sed-Sal at any stimulation frequency. These results demonstrate a beneficial effect of moderate intensity rehabilitation exercise for the maintenance of body composition, cardiac function and diaphragm muscle function following DOX treatment compared to sedentary rats. NIH R01 HL144858, NIH R01 HL146443, NIH HL134621. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.