Sex Differences in Response to Acute Doxorubicin Cardiorespiratory Muscle Dysfunction and Preconditioning Exercise

ABSTRACT Purpose Doxorubicin (DOX) is a potent chemotherapeutic agent whose clinical use is limited due to cardiorespiratory muscle toxicity. The objective of this study was to evaluate sex differences in the severity of DOX myotoxicity and determine the effectiveness of preconditioning exercise to confer protection. Methods Adult male and female Sprague Dawley rats remained sedentary (Sed) or performed two weeks of exercise preconditioning (5 days/week, 60 min/day, 30 m/min) (Ex). Twenty-four hours after the final exercise bout rats received saline (Sal) or DOX (20 mg/kg IP). Forty-eight hours later, cardiac and respiratory muscle function were assessed and tissues were collected. Results Exercise preconditioning increased exercise tolerance in both male and female Sal- and DOX-treated rats compared to their Sed counterpart (Male: Sed-DOX 26.89 ± 2.30 min vs. Ex-DOX 39.01 ± 2.76 min; Female: Sed-DOX 24.65 ± 1.81 min vs. Ex-DOX 45.14 ± 3.72 min). DOX reduced left ventricle fractional shortening (FS%) and maximal diaphragm muscle force production compared to Sal-treated rats in males and females, which were only prevented with exercise in female DOX-treated rats (FS% Male: Sed-DOX 35.57 ± 1.59% vs. Ex-DOX 35.12 ± 0.67%; Female: Sed-DOX 36.84 ± 1.11% vs. Ex-DOX 43.99 ± 2.56% and Force Male: Sed-DOX 17.93 ± 1.13 N/cm 2 vs. Ex-DOX 20.91 ± 1.01 N/cm 2 ; Female: Sed-DOX 19.71 ± 0.68 N/cm 2 vs. Ex-DOX 22.00 ± 1.47 N/cm 2 ). These effects were associated with sex-specific differences in circulating hormones, muscle DOX accumulation and gene expression. Conclusions Cardiorespiratory muscle toxicity occurred following acute DOX exposure in male and female rats. Although, exercise preconditioning elicited a robust increase in cardiorespiratory endurance in both sexes, the beneficial effects of exercise on cardiac and diaphragm muscle function occurred exclusively in female rats.