Insulin Suppresses Atrophy- and Autophagy-related Genes in Heart Tissue and Cardiomyocytes Through AKT/FOXO Signaling

Autor(es)

Paula-Gomes, S. ^[1] ; Goncalves, D. A. P. ^[2] ; Baviera, A. M. ^[3] ; Zanon, N. M. ^[2] ; Navegantes, L. C. C. ^[2] ; Kettelhut, I. C. ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Med, Dept Biochem Immunol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Med, Dept Physiol, Sao Paulo - Brazil

^[3] SAo Paulo Univ State UNESP Araraquara, Sch Pharmaceut Sci, Dept Clin Anal, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Hormone and Metabolic Research; v. 45, n. 12, p. 849-855, NOV 2013.
• Citações Web of Science: 31

Resumo

Insulin is an important regulator of the ubiquitin-proteasome system (UPS) and of lysosomal proteolysis in cardiac muscle. However, the role of insulin in the regulation of the muscle atrophy-related Ub-ligases atrogin-1 and MuRF1 as well as in autophagy, a major adaptive response to nutritional stress, in the heart has not been characterized. We report here that acute insulin deficiency in the cardiac muscle of rats induced by streptozotocin increased the expression of atrogin-1 and MuRF1 as well as LC3 and Gabarapl1, 2 autophagy-related genes. These effects were associated with decreased phosphorylation levels of Akt and its downstream target Foxo3a; this phenomenon is a well-known effect that permits the maintenance of Foxo in the nucleus to activate protein degradation by proteasomal and autophagic processes. The administration of insulin increased Akt and Foxo3a phosphorylation and suppressed the diabetes-induced expression of Ub-ligases and autophagy-related genes. In cultured neonatal rat cardiomyocytes, nutritional stress induced by serum/glucose deprivation strongly increased the expression of Ub-ligases and autophagy-related genes; this effect was inhibited by insulin. Furthermore, the addition of insulin in vitro prevented the decrease in Akt/Foxo signaling induced by nutritional stress. These findings demonstrate that insulin suppresses atrophy- and autophagy-related genes in heart tissue and cardiomyocytes, most likely through the phosphorylation of Akt and the inactivation of Foxo3a. (AU)

• Processo FAPESP: 10/12206-4 - Papel da insulina e do sistema nervoso simpático no controle da geração de glicerol-3-fosfato no tecido adiposo branco de ratos
• Beneficiário: Isis Do Carmo Kettelhut
• Linha de fomento: Auxílio à Pesquisa - Regular
• 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: 12/18861-0 - A hiperacetilação de FOXO como um mecanismo de supressão do programa gênico atrófico pela sinalização adrenérgica beta2 em músculos esqueléticos de roedores
• Beneficiário: Dawit Albieiro Pinheiro Gonçalves
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado