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Potential therapeutic targets induced by aerobic exercise training for the treatment of cancer cachexia: a study of ribosomal proteins

Grant number: 16/26169-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2017
Effective date (End): June 30, 2020
Field of knowledge:Health Sciences - Physical Education
Principal Investigator:Patricia Chakur Brum
Grantee:Marcelo Gomes Pereira
Home Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment, AP.TEM

Abstract

Cancer is among the leading causes of death in most developed countries and is considered as the second leading cause of death in developing countries. With the increase in the life expectancy of the population it is estimated that millions of new cases of cancer will be diagnosed in the coming years. Advances in the diagnosis and treatment of cancer have significantly improved the survival of patients; however, factors such as loss of muscle mass (cancer cachexia) affects tolerability and response to treatment, as well as the prognosis of patients. Thus, cancer cachexia represents a serious public health problem, since it reduces not only the patients' quality of life, but also increases hospitalization costs. In this sense, discovering molecular mechanisms involved in the loss of muscle mass, as well as the use of therapeutic strategies for cancer cachexia are of great scientific relevance. In a previous work of our group (FAPESP # 2014/03016-8 and # 2015/22814-5) the proteomic analysis of skeletal muscle tissue from an experimental model of cachexia identified altered ribosomal proteins in cancer. It was also observed that aerobic exercise training (AET), besides inducing functional benefits, was able to prevent the reduction in the content of ribosomal proteins. Because they have been induced by AET those ribosomal proteins can be studied as a possible targets for the development of therapeutic agents capable to improving muscle function, reducing morbidity and increasing the patient's motor independence. Therefore, the main proposal of this project is the study of the AET-induced targets (ribosomal proteins: Rplp0, Rplp1 and Rpl4) in different cachexia mice models in order to validate them as therapeutic targets. The role of these three ribosomal proteins in the context of cachexia is still unknown; however, it is known that its translation process is controlled by mTORC1. In this sense, we also propose to investigate if through the in vivo manipulation of the Akt/mTORC1 pathway the cachectic muscle still presents some intrinsic conditions to respond adaptively to hypertrophic stimuli. Our main results could contribute to basis for innovative research lines in order to better understand skeletal muscle plasticity and to investigate potential therapeutic approaches necessary to prevent muscle loss.