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INFLUENCE OF AEROBIC PHYSICAL TRAINING ON HEMOXYGENASE-1 IN THE CONTROL OF MUSCLE MASS AND TUMOR GROWTH IN AN EXPERIMENTAL MODEL OF CANCER-INDUCED CACHEXIA.

Grant number: 21/08109-8
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): February 01, 2022
Effective date (End): February 28, 2025
Field of knowledge:Health Sciences - Physical Education
Principal researcher:Patricia Chakur Brum
Grantee:Ailma Oliveira da Paixão
Home Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cancer cachexia is a multifactorial syndrome characterized by loss of muscle mass, a condition that negatively affects the prognosis and quality of life of patients. Skeletal muscle depletion during cancer is related to shorter survival and reduced physical fitness. In addition, muscle atrophy, in general, is associated with contractile dysfunction, both being directly affected by oxidative stress and local and systemic inflammation. In this sense, strategies that reduce the deleterious effects of increased oxidative stress and inflammation in skeletal muscle are of great relevance. Aerobic physical training (AFT) has been recommended as a strategy capable of inducing muscle antioxidant and anti-inflammatory response, attenuating muscle mass loss. Previous data from our laboratory and from the literature demonstrate that TFA reduces tumor mass and volume. Despite this, the mechanisms involved in the effects of TFA on the attenuation of muscle mass and tumor loss still need to be elucidated and are under intense investigation. In proteomic analysis performed in our laboratory, we observed that the Hemopexin/Hemoxygenase system was increased in muscles of animals with high capacity to perform aerobic exercises. This system's main effector is Hemoxygenase-1 (HO-1), whose main function is to maintain cell homeostasis due to its ability to degrade the heme group. Therefore, in a first study, we aim to study the potential contribution of TFA in restoring the expression/activity of HO-1 and its metabolites, carbon monoxide (CO), ferrous iron (Fe2+) and biliverdin (BVD) and minimizing the Muscle atrophy induced by cancer cachexia in mice. Although HO-1 and its metabolites are excellent potential targets associated with TFA in attenuating the loss of muscle mass and function in cachexia due to their antioxidant and anti-inflammatory effects, these effects are not desirable in the tumor mass, as they would accelerate tumor growth. In fact, elevated HO-1 levels are associated with tumor growth, proliferation, metastasis, and malignancy. Therefore, in a second study, we intend to investigate whether TFA can counteract the potential deleterious effects of HO-1 on tumor tissue. Our hypotheses for study 1 and 2 of this project are: 1) TFA will up-regulate HO-1 in cancer-induced skeletal muscle of cachectic animals, attenuating muscle atrophy and 2) TFA in tumor tissue will decrease HO-1 regulation contributing to a decrease in tumor malignancy. For this, BALB/C animals will be randomly randomized into a healthy control group, a cancer cachexia group and an inactive group with cancer that will undergo TFA for 30 days and later be injected with colon cancer tumor cells (CT26) in the subcutaneous region of the animals' upper right flank. Forty-eight hours after cell injection, the animals will resume TFA until the 14th day and on the 16th day the trained animals and those from the healthy and cancer control groups will be killed for skeletal muscle and tumor collection for histological, biochemical and molecular. We hope that with our results we can elucidate the mechanisms by which TFA distinctly modulates HO-1 in the two types of tissues studied in this study, as well as identifying the possible benefits that TFA can bring as an additional therapeutic strategy for the cachectic muscle in colon cancer.

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