Aerobic Exercise During Early Murine Doxorubicin Exposure Mitigates Cardiac Toxicity

Abstract

We report the cardioprotective effects of moderate aerobic exercise from parallel pediatric murine models of doxorubicin (Doxo) exposure in non-tumor-bearing immune competent (NTB-IC) mice and tumor-bearing nude mice (TB-NM). In both models, animals at 4 weeks of age underwent Doxo treatment with or without 2 weeks of simultaneous exercise. In sedentary NTB-IC or TB-NM mice, Doxo treatment resulted in a statistically significant decrease in ejection fraction and fractional shortening compared with control animals. Interestingly, moderate aerobic exercise during Doxo treatment significantly mitigated decreases in ejection fraction and fractional shortening. In contrast, these protective effects of exercise were not observed when exercise was started after completion of Doxo treatments. Moreover, in the TB-NM model, Doxo caused a decrease in heart mass: tibia length and in body weight that was prevented by exercise, whereas NTB-IC mice exhibited no change in these measurements. Doxo delivery to the hearts of TB-NM was decreased by consistent moderate aerobic exercise before Doxo injection. These findings demonstrate the important but subtle differences in cardiotoxicity observed in different mouse models. Collectively, these results also strongly suggest that aerobic exercise during early-life Doxo exposure mitigates cardiotoxicity, possibly through altered delivery of Doxo to myocardial tissue.

Clinical and preclinical evidence of sex-related differences in anthracycline-induced cardiotoxicity

“…AIC is definitely a major contributor to this increased risk of heart failure [ 13 ]. Indeed, pediatric cancer patients face potentially worse outcomes than adult patients as their hearts are still developing during the anthracycline exposure [ 15 ], since neonatal cardiomyocytes are more susceptible to DOX-induced apoptosis than terminally differentiated cardiomyocytes [ 16 ]. Similar to adult cancer patients, the total anthracycline cumulative dose is the major determinant of AIC.…”

“…There is rarity of preclinical animal models of juvenile DOX-induced cardiotoxicity, as compared to adult animal studies [ 15 , 52 – 57 ]. In these few studies, sex was not considered as a biological variable in either the design or the analysis of their findings.…”

Can Exercise-Induced Modulation of the Tumor Physiologic Microenvironment Improve Antitumor Immunity?

“…It is well established that tumor hypoxia contributes to tumor progression, radioresistance, and chemoresistance. Improved perfusion and reduced hypoxia in the tumor microenvironment could improve drug delivery, enhance tumor response to chemotherapy, and lead to better prognosis (12,(16)(17)(18).…”

Doxorubicin-Induced Cardiotoxicity

“…In addition to pharmaceutical measure, lifestyle modifications are promising alternative strategies to counteract DOX-induced cardiomyopathy since it is practical to be introduced to patients. Several types of exercise such as chronic resistance exercise [84], chronic swimming [85], voluntary exercise [86,87], and treadmill running [88][89][90][91] have been shown to exert beneficial effect on mitigation of cardiac structural damage and preservation of cardiac performance in animal models of DOX cardiotoxicity. Moreover, acute exercise prior to DOX treatment protects cardiac function of breast cancer patients [92].…”