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

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 to determine the effectiveness of preconditioning exercise to confer protection.

Adult male and female Sprague-Dawley rats remained sedentary (Sed) or performed 2 wk of exercise preconditioning (5 d·wk -1 , 60 min·d -1 , 30 m·min -1 ) (Ex). Twenty-four hours after the final exercise bout, rats received saline (Sal) or DOX (20 mg·kg -1 IP). Forty-eight hours later, cardiac and respiratory muscle functions were assessed and tissues were collected.

Exercise preconditioning increased exercise tolerance in both male and female Sal- and DOX-treated rats compared with 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 with 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 after 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.