Involvement of cAMP/Epac/PI3K-dependent pathway in the antiproteolytic effect of epinephrine on rat skeletal muscle

Autor(es)

Baviera, Amanda Martins ^[1] ; Zanon, Neusa Maria ^{[2, 3]} ; Navegantes, Luiz Carlos C. ^{[2, 3]} ; Kettelhut, Isis Carmo ^{[2, 3]}

Afiliação do(s) autor(es)

^[1] Univ Fed Mato Grosso, Dept Chem, BR-78060900 Cuiaba, MT - Brazil

^[2] USP, Dept Biochem & Immunol, Sch Med, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] USP, Dept Physiol, Sch Med, BR-14049900 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Molecular and Cellular Endocrinology; v. 315, n. 1-2, p. 104-112, FEB 5 2010.
• Citações Web of Science: 30

Resumo

Very little is known about the signaling pathways by which catecholamines exert anabolic effects on muscle protein metabolism, stimulating protein synthesis and suppressing proteolysis. The present work tested the hypothesis that epinephrine-induced inhibition of muscle proteolysis is mediated through the cAMP/Epac/PI3K-dependent pathway with the involvement of AKT and Foxo. The incubation of extensor digitorum longus (EDL) muscles from rats with epinephrine and/or insulin increased the phosphorylation of AKT and its downstream target Foxo3a, a well-known effect that prevents Foxo translocation to the nucleus and the activation of proteolysis. Similar effects on AKT/Foxo signaling were observed in muscles incubated with DBcAMP (cAMP analog). The stimulatory effect of epinephrine on AKT phosphorylation was completely blocked by wortmannin (selective PI3K inhibitor), suggesting that the epinephrine-induced activation of AKT is mediated through PI3K. As for epinephrine and DBcAMP, the incubation of muscles with 8CPT-2Me-cAMP (selective Epac agonist) reduced rates of proteolysis and increased phosphorylation levels of AKT and Foxo3a. The specific PKA agonist (N6BZ-cAMP) inhibited proteolysis and abolished the epinephrine-induced AKT and Foxo3a phosphorylation. On the other hand, inhibition of PKA by H89 further increased the phosphorylation levels of AKT and Foxo3a induced by epinephrine, DBcAMP or 8CPT-2Me-cAMP. These findings suggest that the antiproteolytic effect of the epinephrine on isolated skeletal muscle may occur through a cAMP/Epac/PI3K-dependent pathway, which leads to the phosphorylation of AKT and Foxo3a. The parallel activation of PKA-dependent pathway also inhibits proteolysis and seems to limit the stimulatory effect of cAMP on AKT/Foxo3a signaling. (C) 2009 Elsevier Ireland Ltd. All rights reserved. (AU)

• Processo FAPESP: 08/06694-6 - Controle neural do metabolismo de proteínas
• Beneficiário: Isis Do Carmo Kettelhut
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 06/06974-3 - Controle hormonal do metabolismo de proteinas em musculo esqueletico: papel da via pi3k/akt na regulacao da proteolise muscular pela insulina e catecolaminas.
• Beneficiário: Isis Do Carmo Kettelhut
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 06/56918-2 - Papel da via pi3k/akt na regulacao da proteolise muscular pela insulina e catecolaminas.
• Beneficiário: Amanda Martins Baviera
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 03/13080-0 - Controle hormonal do metabolismo de proteinas em musculo esqueletico: papel das catecolaminas no sistema proteolitico dependente de calcio em musculo esqueletico de ratos normais e diabeticos.
• Beneficiário: Isis Do Carmo Kettelhut
• Modalidade de apoio: Auxílio à Pesquisa - Regular