Response to treatment with metformin and endurance exercise in mitigating muscle disorders induced by doxorubicin therapy.

Author(s)

Edson Alves de Lima Junior

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2020-12-14

Examining board members

José Cesar Rosa Neto; Alison Colquhoun; Marcelo Damario Gomes; Gustavo Duarte Pimentel

• Advisor: José Cesar Rosa Neto

Abstract

The administration of doxorubicin has been widely used in the treatment of cancer. However, its use is limited due to the manifestation of adverse side effects such as muscle loss. Based on the evidence that many types of cancer are treated with this chemotherapy, the aim of the present study was to investigate the effect of strategies that could potentially be able to minimize muscle disorders caused by this anthracycline. For this, C57BL / 6 mice received saline solution (CT) or were submitted to treatment with doxorubicin (DOX) for 6 weeks. The DOX group was further subdivided into animals that performed endurance exercise on treadmill (DOX + EXER) or received metformin (DOX + MET). The combination with endurance exercise increased AMPk activity in the gastrocnemius muscle, improved physical performance on treadmill and protected against the increase in corticosterone. The association with metformin only normalized the concentration of corticosterone. Subsequently, we investigated the effect of the association of endurance exercise in a short period of treatment with doxorubicin in mice with tumor, establishing the effect of the interruption of chemotherapy on skeletal muscle. One week after the establishment of Lewis lung carcinoma (LLC group), part of the animals were subjected to chemotherapy treatment with doxorubicin (LLC + DOX) or subjected to chemotherapy combined with endurance exercise (LLC + DOX + EXER). Euthanasia occurred at the end of the chemotherapy cycle or one week after the last administration of doxorubicin. With the interruption of chemotherapy treatment, endurance exercise minimized the resumption of tumor growth rate, decreased the muscle loss and prevented the increased expression of proteins involved in muscle catabolism (MuRF1, Atrogin1, Myostatin and FoxO) in relation to the isolated treatment with doxorubicin. The results obtained indicate that the combination of endurance exercise during treatment with doxorubicin partially reversed the adverse effects of this chemotherapy, resulting in protection against the loss of muscle performance and normalization of the corticosterone concentration. More consistent effects were found with the continuity of endurance exercise after the interruption of chemotherapy, which, even in the presence of the tumor, minimized muscle loss by decreasing catabolism, reduced the resumption of tumor growth and prevented reduced survival. (AU)

• FAPESP's process: 15/17068-2 - Effect of aerobic exercise training associated with doxorubicin chemotherapy in mice with Lewis lung carcinoma (LLC). Role of adiponectin in skeletal muscle and tumor.
• Grantee: Edson Alves de Lima Junior
• Support Opportunities: Scholarships in Brazil - Doctorate