Abstract Body (Do not enter title and authors here): Background: Increasing physical activity (PA) mitigates left ventricular (LV) declines in breast cancer patients undergoing Anthracycline (Anth) treatment. There is evidence that Anth induces mitochondrial dysfunction in cardiac and skeletal muscle (SM), contributing to LV dysfunction. However, the underlying mechanisms by which PA may be an effective therapy remain elusive.
Objective: To evaluate the association between cardiac and SM mitochondrial function with LV function of mice treated with Anth. We hypothesize exercise improves mitochondrial function which ameliorates Anth-induced tissue injury.
Methods: Twenty 12-week-old female mice treated with 5 mg/kg of doxorubicin (Dox, IP once a week for 4 weeks) were randomized to low-intensity treadmill exercise (Dox+Ex) or no exercise (Dox+no-Ex). In a blinded analysis, we measured LV function by echocardiography (LV ejection fraction, LVEF) before and after Dox treatment. At the experimental endpoint, tissues were collected to measure LV collagen volume fraction (CVF) and high-resolution respirometry (Oroboros, O₂ flux per mass pmol/(s*mg)) of LV and SM. An additional cohort of mice injected with saline that did not exercise (Saline-no-Ex, n=5) were used as controls for respirometry experiments.
Results: Animals that did not exercise during Dox treatment experienced LV dysfunction (Pre-Dox: 66.6±2.9% vs. Post-Dox: 57.4±7.2%, p=0.01), while exercise ameliorated such declines (Pre-Dox: 67.2±3.8% vs. Post-Dox: 66.5±7.8%, p=0.43). Mice that exercised experienced lower levels of CVF (Dox+Ex: 0.9±0.1 % vs. Dox-no-Ex: 1.5±0.5%; p<0.02). Importantly, mice treated with Dox that did not exercise exhibited lower complex I maximal respiratory capacity (CI-Max) compared to controls (Dox+no-Ex: 29.4±25.5 vs. Saline-no-Ex: 92.3±56.1, p= 0.04) and exercise during Dox treatment prevented such declines (Dox+no-Ex: 29.37±25.45 vs. Dox+Ex: 139.6±66.3 p=0.01). There were no changes in CI-Max in SM between groups (p>0.05). Cardiac tissue CI-Max was significantly correlated with post-Dox LVEF (r=0.82, p=0.03). No associations were observed between LVEF and SM CI-max (p=0.66).
Conclusions: Exercise mitigated LV dysfunction, cardiac fibrosis, and cardiac CI-linked respiration declines after Dox treatment. Our results add to the evidence suggesting that exercise may be an effective therapy to prevent Anth-induced LV dysfunction in patients undergoing Anth therapies. Mitochondrial complex I represents a promising therapeutic target.