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

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.