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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Mechanisms Involved in 3 `,5 `-Cyclic Adenosine Monophosphate-Mediated Inhibition of the Ubiquitin-Proteasome System in Skeletal Muscle

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Autor(es):
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Goncalves, Dawit A. P. [1, 2] ; Lira, Eduardo C. [1, 2] ; Baviera, Amanda M. [3] ; Cao, Peirang [4, 5] ; Zanon, Neusa M. [1, 2] ; Arany, Zoltan [4, 5] ; Bedard, Nathalie [6] ; Tanksale, Preeti [4, 5] ; Wing, Simon S. [6] ; Lecker, Stewart H. [4, 5] ; Kettelhut, Isis C. [1, 2] ; Navegantes, Luiz C. C. [1, 2]
Número total de Autores: 12
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Dept Physiol, Sch Med, BR-14049900 Ribeirao Preto - Brazil
[2] Univ Sao Paulo, Dept Biochem & Immunol, Sch Med, BR-14049900 Ribeirao Preto - Brazil
[3] Univ Fed Mato Grosso, Dept Chem, BR-78060900 Cuiaba - Brazil
[4] Beth Israel Deaconess Med Ctr, Dept Med, Div Renal, Boston, MA 02215 - USA
[5] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiol, Boston, MA 02215 - USA
[6] McGill Univ, Dept Med, Polypeptide Lab, Montreal, PQ H3A 2B2 - Canada
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: Endocrinology; v. 150, n. 12, p. 5395-5404, DEC 2009.
Citações Web of Science: 29
Resumo

Although it is well known that catecholamines inhibit skeletal muscle protein degradation, the molecular underlying mechanism remains unclear. This study was undertaken to investigate the role of beta(2)-adrenoceptors (AR) and cAMP in regulating the ubiquitin-proteasome system (UPS) in skeletal muscle. We report that increased levels of cAMP in isolated muscles, promoted by the cAMP phosphodiesterase inhibitor isobutyl methylxanthine was accompanied by decreased activity of the UPS, levels of ubiquitin-protein conjugates, and expression of atrogin-1, a key ubiquitin-protein ligase involved in muscle atrophy. In cultured myotubes, atrogin-1 induction after dexamethasone treatment was completely prevented by isobutyl methylxanthine. Furthermore, administration of clenbuterol, a selective beta(2)-agonist, to mice increased muscle cAMP levels and suppressed the fasting-induced expression of atrogin-1 and MuRF-1, atrogin-1 mRNA being much more responsive to clenbuterol. Moreover, clenbuterol increased the phosphorylation of muscle Akt and Foxo3a in fasted rats. Similar responses were observed in muscles exposed to dibutyryl-cAMP. The stimulatory effect of clenbuterol on cAMP and Akt was abolished in muscles from beta(2)-AR knockout mice. The suppressive effect of beta(2)-agonist on atrogin-1 was not mediated by PGC-1 alpha (peroxisome proliferator-activated receptor-gamma coactivator 1 alpha known to be induced by beta(2)-agonists and previously shown to inhibit atrogin-1 expression), because food-deprived PGC-1 alpha knockout mice were still sensitive to clenbuterol. These findings suggest that the cAMP increase induced by stimulation of beta(2)-AR in skeletal muscles from fasted mice is possibly the mechanism by which catecholamines suppress atrogin-1 and the UPS, this effect being mediated via phosphorylation of Akt and thus inactivation of Foxo3. (Endocrinology 150: 5395-5404, 2009) (AU)

Processo FAPESP: 08/06694-6 - Controle neural do metabolismo de proteínas
Beneficiário:Isis Do Carmo Kettelhut
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 06/06974-3 - Controle hormonal do metabolismo de proteínas em músculo esquelético: papel da via PI3K/Akt na regulação da proteólise muscular pela insulina e catecolaminas
Beneficiário:Isis Do Carmo Kettelhut
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 04/02674-0 - Controle da perda de proteínas musculares em situações catabólicas: um estudo de microdiálise
Beneficiário:Luiz Carlos Carvalho Navegantes
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
Processo FAPESP: 09/07584-2 - Papel das vias de sinalização da Akt/Foxo e MEK/ERK no efeito antiatrófico mediado pelos adrenoceptores B2 em músculo esquelético de roedores
Beneficiário:Dawit Albieiro Pinheiro Gonçalves
Linha de fomento: Bolsas no Brasil - Doutorado