The Use of Exercise to Mitigate Cardiotoxic Effects of Doxorubicin Treatment in Male and Female Rats

PURPOSE: The clinical use of doxorubicin (DOX) as a chemotherapeutic agent is severely limited by cardiotoxicity. Following treatment, DOX can accumulate within cardiomyocytes leading to mitochondrial dysfunction and heart failure. Interestingly, exercise has been shown to limit DOX cardiotoxicity. However, no current study considers sex in this paradigm. METHODS: Adult male and female Sprague Dawley rats underwent a 2-week treadmill preconditioning program (5 days/week, 60 min/day, 30 m/min, 0% grade). Twenty-four hours after the final exercise bout, rats were randomly assigned to receive saline (SAL) or DOX (20 mg/kg IP) with endpoint 48 hours later. Analyses were separated by sex and a 2x2 ANOVA was performed to determine main effects (ME) of treatment (SAL vs. DOX, p < 0.05) and/ or activity (sedentary (SED) vs. exercise (EX), p < 0.05). Where significant interactions were noted (p < 0.05), Sidak’s multiple comparisons test was performed. RESULTS: Males demonstrated a ME of treatment and activity on bodyweight (BW) and a significant increase in BW in SED-EX vs. SED-SAL rats (SED-SAL -5.6 ± 1.5 g; EX-SAL +7.0 ± 1.3 g; SED-DOX -19.4 ± 1.7 g; EX-DOX -21.0 ± 2.9 g). Females only showed a ME of treatment on BW (SED-SAL -1.7 ± 2.7 g; EX-SAL +1.1 ± 3.5 g; SED-DOX -8.0 ± 1.8 g; EX-DOX -5.0 ± 3.7 g). Heart weight/ tibia length in males revealed a ME of treatment with no activity effect (SED-SAL 22.8 ± 0.5 mg/mm; EX-SAL 22.0 ± 0.3 mg/mm; SED-DOX 20.6 ± 0.5 mg/mm; EX-DOX 19.8 ± 0.8 mg/mm), with no difference in females (SED-SAL 16.6 ± 0.9 mg/mm; EX-SAL 19.4 ± 0.8 mg/mm; SED-DOX 17.1 ± 1.6 mg/mm; EX-DOX 17.1 ± 0.5 mg/mm). Cardiac mitochondrial function measured via maximal complex I-linked (malate/pyruvate) oxygen flux (JO2) was not different in males (SED-SAL 6986.6 ± 732.3 pmol/s/mg; EX-SAL 6356.7 ± 950.7 pmol/s/mg; SED-DOX 7010.2 ± 1218.6 pmol/s/mg; EX-DOX 6655.4 ± 1308 pmol/s/mg). Contrastingly, females significantly increased complex I JO2 in EX-DOX (7287.8 ± 618.8 pmol/s/mg) vs. SED-DOX (4671.8 ± 749.1 pmol/s/mg) rats, without differences between SED-SAL (7198.8 ± 958.6 pmol/s/mg) and EX-SAL (6324.8 ± 847.7 pmol/s/mg). CONCLUSION: The effects of DOX and exercise preconditioning are differentiated by sex, with males demonstrating greater effects to BW and heart mass, and females showing greater changes in mitochondrial respiration.