Exercise Reduces the Resumption of Tumor Growth and Proteolytic Pathways in the Skeletal Muscle of Mice Following Chemotherapy.

Simple Summary Doxorubicin is a chemotherapeutic agent that contributes to muscle wasting. Based on the evidence that many cancer variants are associated with cachexia and that cancer patients are usually treated with chemotherapeutic agents, it is important to determine strategies to mitigate muscle atrophy. Muscle loss is a poor prognosis during cancer treatment, and exercise has emerged as a potential strategy utilized in this context. Once an ongoing regimen of chemotherapeutic treatment is not always possible, our results demonstrated that continuity of endurance exercise is a potential strategy that can be adopted when chemotherapy needs to be interrupted, minimizing the resumption of tumor growth and avoiding muscle loss. The pathogenesis of muscle atrophy plays a central role in cancer cachexia, and chemotherapy contributes to this condition. Therefore, the present study aimed to evaluate the effects of endurance exercise on time-dependent muscle atrophy caused by doxorubicin. For this, C57 BL/6 mice were subcutaneously inoculated with Lewis lung carcinoma cells (LLC group). One week after the tumor establishment, a group of these animals initiated the doxorubicin chemotherapy alone (LLC + DOX group) or combined with endurance exercise (LLC + DOX + EXER group). One group of animals was euthanized after the chemotherapy cycle, whereas the remaining animals were euthanized one week after the last administration of doxorubicin. The practice of exercise combined with chemotherapy showed beneficial effects such as a decrease in tumor growth rate after chemotherapy interruption and amelioration of premature death due to doxorubicin toxicity. Moreover, the protein degradation levels in mice undergoing exercise returned to basal levels after chemotherapy; in contrast, the mice treated with doxorubicin alone experienced an increase in the mRNA expression levels of the proteolytic pathways in gastrocnemius muscle (Trim63, Fbxo32, Myostatin, FoxO). Collectively, our results suggest that endurance exercise could be utilized during and after chemotherapy for mitigating muscle atrophy promoted by doxorubicin and avoid the resumption of tumor growth.