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Master's Dissertation
Full name
Vanessa Fonseca Vilas Boas
Knowledge Area
Date of Defense
São Paulo, 2008
Moriscot, Anselmo Sigari (President)
Aoki, Marcelo Saldanha
Nunes, Maria Tereza
Title in Portuguese
Efeito da triiodotironina (T3) e do agonista TRb seletivo GC-24 sobre o trofismo muscular esquelético de ratos: aspectos envolvendo a proteólise dependente de proteassoma.
Keywords in Portuguese
Hormônios de tireóide
Músculo esquelético
Abstract in Portuguese
O objetivo deste estudo foi investigar os efeitos do T3 e do seu análogo GC-24, agonista TRb seletivo, na proteólise muscular mediada pela via ubiquitina-proteassoma. Avaliamos o efeito do T3 e GC-24 no trofismo radial de fibras musculares, no nível de ubiquitinação e na expressão de genes envolvidos na via ubiquitina-proteassoma. Para tanto foram utilizados, ratos Wistar divididos em 4 grupos (Controle, 12 horas, 1 e 7 dias) e tratados com T3 e GC-24. Determinou-se a área de secção transversa dos cortes histológicos através do programa "Image Pro-Plus". O nível de ubiquitinação foi determinado através de Western Blot para proteína ubiquitinada e a expressão gênica por PCR em Tempo real. T3 e GC-24 promoveram redução do diâmetro das fibras musculares e aumentaram o nível de proteínas ubiquitinadas em ambos os músculos. Com relação à expressão gênica, T3 e GC-24 modularam a expressão dos genes analisados de maneira diferenciada, demonstrando que GC-24 é capaz de modular genes pouco ou não responsivos ao T3.
Title in English
Effect of the triiodothyronine (T3) and the thyroid receptor beta selective agonist GC-24 upon rat skeletal muscle trophism: expression of proteasome-dependent genes.
Keywords in English
Skeletal muscle
Thyroid hormone
Abstract in English
Triiodothyronine (T3) is known to play a key role in the function of several tissues/organs via the thyroid hormone receptor isoforms a/pha (TRa) and beta (TRI3). Abnormalities in skeletal muscle function have been associated with increased leveis of T3, which is a major sarcopenia (Ioss of sarcomeres). Although the phenomenon of sarcopenia induced by T3 has been widely reported, little is known about the molecular mechanisms invo/ved in proteolysis induced by T3. In this study we have investigated the effects of T3 and GC-24, a novel synthetic TRI3¬selective compound, on the ubiquitin proteasome pathway. We analyzed the effect of T3 and GC-24 on the radial trophism, ubiquitination leveis and gene expression of the ubiquitin-proteasome pathway, which are important regulators of muscle proteolysis in the skeletal muscle. We have addressed the ubiquitin ligases (Atrogin¬1, MuRF-1 and E3a) and the deubiquitinating enzymes (UBP45, UBP69 and USP28). Wistar male rats (170-200g) were divided in 4 groups (Control, 12, 1 and 7 days). Rats received T3 (30l-'g/100g) and GC-24 (16 I-'g/1 OOg). After decapitation, EDL and soleus muscles were removed for histological ana/ysis, protein expression and gene expression. Cross sectional area was determined in histological sections through the software "Image-Pro Plus. The ubiquitination leveis was determined by Western Blot and gene expression determined by Real Time PCR analysis. T3 and GC-24 reduced the diameter of the muscle fibers vs control group. Both T3 and GC-24 incresed the ubiquitination leveis, in the soleus and EDL. Regarding gene expression analysis, T3 and GC-24 modulate the gene expression in a differential manner. In the soleus, T3 increased Atrogin-1 and E3 alpha gene expression, while did not alter Murf-1 gene expression. On the other hand, in EDL Atrogin-1 gene expression is not altered, while E3 alpha and Murf-1 are elevated by T3. In the soleus and EDL deubiquitinating gene expression is mostly not altered, exception made for UBP 45, which is reduced by T3 in soleus muscle. GC-24, increased gene expression of E3a and MuRF-1 in the soleus, while did not alter Atrogin-1 gene expression. However, in EDL muscle, GC-24 increased Atrogin-1 and E3a mRNA, while did not alter MuRF-1. Finally, GC-24 decreased UBP 45 gene expression in EDL muscle and USP 28 gene expression was robustly elevated by GC-24 in both muscles analyzed. This data shows that GC-24 is able to strongly modulate genes that are less responsive or even unresponsive to T3, pointing that the GC-24-TRb complex might trans-activate differently target genes. However, both T3 and GC-24 are able to modulate the muscle proteolysis.
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