Avaliação bioquímica, morfológica e funcional do catabolismo muscular associado ao cancro da mama: o papel do exercício físico

Cachexia is one of the most debilitating and life-threatening aspects of cancer affecting about two million patients worldwide. The clinical features which characterize this multi-factorial paraneoplastic syndrome are progressive weight loss, anorexia, metabolic alterations and asthenia. Weight loss is often a presenting feature of cancer and when reaches 30% is generally fatal. Underlying this cancer cachexia-induced weight loss is the wasting of skeletal muscle, the major reservoir of body proteins. Although its causal mechanisms have not been completely elucidated, it has been suggested that this catabolic syndrome is mediated by tumor- and host-released factors. These mediators seem to trigger the imbalance between protein synthesis and breakdown leading to protein depletion and, consequently, muscle wasting, whose degree is inversely correlated with the survival time of patients. Thus, interventions to preserve muscle mass have important clinical implications in terms of improving the prognosis and the quality of life of cancer patients. Current preventive and therapeutic options are largely ineffective. Among non-pharmacologial interventions that may potentially attenuate muscle wasting in cancer patients is physical exercise training. Nevertheless, more data is needed to support this hypothesis.We aim to define the biochemical and molecular mechanisms underlying cancer-induced muscle wasting and analyse the role of physical exercise in its regulation. To address this aim, we will use an animal model of cachexia. Mammary carcinoma will be chemically induced in female rats with the carcinogen 1-methyl-1-nitrosureia (MNU). After the full characterization of the animal model in terms of mortality rate, food intake (anorexia), maximum rates of body and skeletal muscle weight loss, a longitudinal analysis of cancer-induced muscle wasting is proposed. Three groups of female Sprague-Dawley rats will be isolated: a group administrated with MNU (50mg/Kg), a control group and a pair-fed group. The inclusion of this last group will allow the control of the anorexia effect. Subgroups will be created to test the role of exercise, specifically treadmill running. Sacrifices will occur in the beginning and at the end of the cachexia process. Following, blood, tumor tissue and skeletal muscles will be collected for subsequent biochemical and/or morphological analysis. The analysis of serum cytokines, hormones and metabolites and the urinary proteolysisinducing factor (PIF) will give a systemic perspective of the animal body\\\\\\\'s response to cancer and will allow the establishment of groups’ catabolic phenotype. Tumor anatomo- and histopathological analysis will be performed to evaluate mammary carcinoma incidence, which will be further correlated with the general cachexia profile. The major focus of our proposal will be in skeletal muscle wasting response. Biochemical and morphological markers of protein synthesis and breakdow and muscle metabolism will be analysed and correlated with muscle mass, fiber cross-sectional area and phenotype. This comprehensive methodological approach will only befeasible with a multidisciplinary team like the one that integrates this proposal, which will be further supported by national and international consultants from the muscle physiology and oncology fields. We believe that the integration of all data will highlight the cellular pathways underlying the tumor-host interaction that culminates in cachexia. We also expect to mechanistically justify the effectiveness of exercise as a non-pharmacological intervention for cancer cachexia-induced muscle wasting.