Functional and Molecular Skeletal Muscle Responses to Aerobic Exercise in Rat Models of Acute and Chronic Doxorubicin Exposure

This study examined the effects of aerobic exercise on skeletal muscle function, structure, and molecular markers following acute and chronic doxorubicin (DOX) exposure. Fifty-six male Wistar rats were assigned to acute (20 mg/kg, single dose) or chronic DOX (5 mg/kg/week, 3 doses) protocols. In both protocols, rats were allocated in 4 groups: Control (C, n=6), Control Exercise (Control Ex, n=6), DOX (DOX, n=8), and DOX Exercise (DOX Ex, n=8). A 4-week aerobic exercise was performed on a treadmill before acute DOX (preconditioning) or during chronic DOX treatment (concomitant). Muscle function was assessed by electrical stimulation and tibialis anterior muscle was analyzed. Data were analyzed using two-way ANOVA (p<0.05). Acute DOX significantly reduced body and muscle mass, increased low-frequency muscle torque, and impaired muscle relaxation, accompanied by calpain-mediated proteolysis and increased p67phox and catalase expression. Exercise preconditioning significantly reduced circulating basal creatine kinase and modulated SERCA1 expression in skeletal muscle. Chronic DOX significantly reduced body mass, muscle mass, size and function, with a significant increase in plasma malondialdehyde. Inflammatory cytokines were significantly elevated only acutely. Concomitant exercise significantly attenuated calpain-mediated proteolysis in DOX-treated rats and increased glutathione peroxidase expression in control animals. In conclusion, DOX induced skeletal muscle dysfunction with acute alterations in proteins involved in calcium regulation. In the chronic model, DOX induced muscle atrophy, muscle dysfunction, and systemic oxidative stress. While aerobic exercise attenuated calpain-mediated proteolysis in both acute and chronic models, only exercise preconditioning increased SERCA1 expression, highlighting the importance of exercise timing for mitigating DOX-induced muscle alterations.