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Doctoral Thesis
DOI
10.11606/T.41.2012.tde-12072012-160427
Document
Author
Full name
Carlos Roberto Bueno Júnior
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2011
Supervisor
Committee
Zatz, Mayana (President)
Haddad, Luciana Amaral
Medeiros, Alessandra
Okamoto, Oswaldo Keith
Ramires, Paulo Rizzo
Title in Portuguese
Abordagens terapêuticas em modelo experimental de distrofia muscular
Keywords in Portuguese
Distrofias musculares
Tratamentos
Abstract in Portuguese
As distrofias musculares são doenças genéticas causadas por mutações em diferentes genes caracterizadas por degeneração muscular, prejuízos locomotores e, geralmente, morte precoce. Dentre elas, a de Duchenne, causada por mutações no gene que codifica para a proteína distrofina, é a mais comum e grave, tendo os camundongos MDX como modelo experimental mais utilizado. O objetivo do presente estudo foi testar quatro abordagens terapêuticas potencias neste modelo animal, divididas em dois experimentos: 1. treinamento físico voluntário em roda de atividade e/ou drogas agonistas das proteínas AMPK e PPAR em dias alternados (AICAR: 100 mg.Kg-1.dia-1, ip; GW 1516: 5 mg.Kg-1.dia-1, gavagem); 2. células-tronco estromais humanas provenientes de lipoaspiração (um milhão a cada injeção intravenosa; uma injeção a cada 10 dias nos dois primeiros meses de tratamento e injeções mensais nos quatro meses subsequentes) e/ou suplementação com os aminoácidos alanina e glutamina (10 mg.kg-1.dia-1, injeção diária intraperitoneal). Em relação ao primeiro experimento, o principal achado foi que os animais submetidos ao treinamento físico associado às drogas apresentaram índices de função muscular superiores aos outros grupos. Já em relação ao segundo grupo de análises, foi observado que os animais submetidos à terapia celular apresentaram tempo de vida significativamente maior quando comparados aos animais não tratados e aos tratados com ambas as terapias. Tais resultados, nunca demonstrados previamente pela literatura científica, podem contribuir para o entendimento da fisiopatologia das distrofias musculares e para o avanço de potenciais abordagens terapêuticas.
Title in English
Therapeutic approaches in an experimental model of muscular dystrophy
Keywords in English
Muscular dystrophies
Treatments
Abstract in English
Muscular dystrophies are genetic diseases caused by mutations in different genes. They are characterized by muscle degeneration, motor prejudices and, generally, early death. Among them, Duchenne muscular dystrophy (DMD) is the most common and severe form and it is caused by mutations in the dystrophin gene. The most widely used animal model of DMD is the MDX mouse. The aim of this study was to test four potential therapeutic approaches assigned in two experiments: 1. voluntary exercise training in activity road and/or AMPK and PPAR agonists drugs every other day in MDX mice (AICAR: 100 mg.Kg-1.day-1, IP; GW 1516: 5 mg.Kg-1.day-1, gavage); 2. Intravenous injection of stromal stem cells from human adipose tissue (106 cells every 10 days in the first two months and monthly injections in the following four months) and/or alanine and glutamine amino acids supplementation (10 mg.Kg-1.day-1, daily IP injections). In the first experiment we demonstrated that mdx mice submitted to exercise training associated to drugs presented improved muscle function when compared to the other groups. In the second experiment, on the other hand, it was observed that the animals submitted to cell therapy presented increased survival when compared to non injected animals and animals treated with both approaches. These results, here demonstrated for the first time, can contribute to understand the physiopathology of muscular dystrophies and may give insights for future therapeutic approaches
 
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Carlos_BuenoJr.pdf (1.15 Mbytes)
Publishing Date
2012-08-03
 
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