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Doctoral Thesis
DOI
10.11606/T.42.2018.tde-22022018-141618
Document
Author
Full name
Juliane Cruz Campos
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2017
Supervisor
Committee
Ferreira, Julio Cesar Batista (President)
Evangelista, Fabiana de Sant'Anna
Ferro, Emer Suavinho
Festuccia, William Tadeu Lara
Silveira, Leonardo dos Reis
Title in Portuguese
Controle de qualidade de proteína na disfunção/atrofia muscular esquelética: papel do receptor β2-adrenérgico.
Keywords in Portuguese
Autofagia
Controle de qualidade de proteína
Músculo esquelético
Proteassoma
Receptor adrenérgico
Abstract in Portuguese
O Controle de qualidade de proteína (CQP) consiste na supervisão e no processamento de proteínas danificadas por meio de processos catalíticos (proteassoma e autofagia). Nesse estudo, caracterizamos o CQP, bem como os benefícios da ativação β2-adrenérgica (β2-AR) modulador positivo do CQP, em modelo animal de disfunção/atrofia muscular induzida por constrição crônica do nervo isquiático (CCI). Observamos que, apesar de um aumento na atividade catalítica, a atrofia está associada à um CQP insuficiente, detectado por um acúmulo de proteínas citotóxicas nessa musculatura. O tratamento com Formoterol (agonista β2-AR) aumentou a atividade proteassomal e restaurou o fluxo de degradação via autofagia, resultando na melhora do CQP e da miopatia esquelética. A inibição da autofagia, mas não do proteassoma, foi capaz de abolir os efeitos do Formoterol na CCI. Nossos resultados sugerem uma nova contribuição da sinalização β2-AR no quadro de miopatia esquelética, no qual sua ativação foi capaz de restaurar o CQP, contribuindo para a melhora do trofismo e função muscular.
Title in English
Protein quality control in skeletal muscle weakness/wasting: role of β2-adrenoceptor.
Keywords in English
Adrenoceptor
Autophagy
Proteasome
Protein quality control
Skeletal muscle
Abstract in English
The protein quality control (PQC) detects, repairs and disposes cytotoxic proteins through different proteolytic systems (proteasome and autophagy). Here, we characterized the PQC profile as well as the benefits of sustained β2-adrenoceptor activation (β2-AR) a positive PQC modulator, during skeletal muscle atrophy in a rat model of sciatic nerve constriction (SNC). PQC is disrupted in SNC rats, demonstrated by elevated proteasomal and lysosomal activities along with accumulation of cytotoxic proteins and pro-apoptotic factors. The β2-AR activation (Formoterol) promotes a further increase in proteasomal activity, along with autophagic flux reestablishment. Of interest, sustained autophagy inhibition, but not proteasomal inhibition, is sufficient to abolish Formoterol effects on skeletal muscle PQC, mass and strength. These findings suggest a new contribution of β2-AR signalling pathway to the pathophysiology of skeletal muscle where β2-AR restores the impaired PQC, therefore contributing to a better skeletal muscle morphology and function.
 
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Release Date
2020-05-03
Publishing Date
2018-05-04
 
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