# Preventive Aerobic Training Protects Against Doxorubicin-Induced Cardiotoxicity by Preserving Redox Status and Attenuating Cardiac Stress-Related Signaling

## TL;DR

Aerobic training before chemotherapy protects the heart by reducing oxidative stress and inflammation caused by doxorubicin.

## Contribution

This study shows that preventive aerobic training mitigates doxorubicin-induced cardiotoxicity through redox preservation and reduced cardiac stress signaling.

## Key findings

- Preventive aerobic training improved exercise capacity and preserved antioxidant enzyme activity in rats.
- Training attenuated doxorubicin-induced increases in IL-1β and HIF-1 expression in cardiac tissue.
- Aerobic training partially prevented doxorubicin-induced cardiac atrophy and reduced apoptotic signaling.

## Abstract

Doxorubicin (DOX) is a highly effective chemotherapeutic agent whose clinical use is limited by dose-dependent cardiotoxicity associated with oxidative stress, inflammation, and cellular stress responses. Here, we investigated whether preventive aerobic training could protect against DOX-induced cardiac injury in Wistar rats. Animals were assigned to sedentary control (C), sedentary DOX (D), trained control (CT), and trained DOX (DT) groups. The moderate-intensity (~50–80% maximal exercise test) treadmill protocol (40 min/day, 4 days/week for 4 weeks) was performed before intraperitoneal administration of DOX (4 mg/kg, weekly for 4 weeks) or saline. Preventive training markedly improved exercise capacity (p < 0.001) and attenuated oxidative damage, maintaining antioxidant enzyme activity (GR, SOD) at control levels (p > 0.05). DOX significantly upregulated cardiac IL-6 and IL-1β expression (p < 0.01), while trained animals preserved IL-1β expression similar to controls (p > 0.99). In parallel, DOX increased cardiac HIF-1 expression (p < 0.05), indicating activation of hypoxia- and stress-related signaling pathways, an effect that was attenuated by preventive training (p > 0.99). DOX-induced cardiac atrophy was evidenced by reduced left ventricular mass (p < 0.001), which was partially prevented by training (p < 0.05). Although hematological toxicity persisted, preventive aerobic exercise effectively counteracted DOX cardiotoxicity by restoring redox homeostasis, dampening inflammation, and limiting apoptotic signaling. Collectively, these findings highlight exercise preconditioning as a promising non-pharmacological strategy in cardio-oncology to mitigate chemotherapy-associated cardiac injury.