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Horm Metab Res 2013; 45(12): 849-855
DOI: 10.1055/s-0033-1347209
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

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

S. Paula-Gomes
1   Department of Biochemistry/Immunology, School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
,
D. A. P. Gonçalves
2   Department of Physiology, School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
,
A. M. Baviera
3   Department of Clinical Analysis, School of Pharmaceutical Sciences, São Paulo University State (UNESP – Araraquara), Araraquara, São Paulo, Brazil
,
N. M. Zanon
2   Department of Physiology, School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
,
L. C. C. Navegantes
2   Department of Physiology, School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
,
I. C. Kettelhut
1   Department of Biochemistry/Immunology, School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
2   Department of Physiology, School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
› Author Affiliations
Further Information

Publication History

received 26 March 2013

accepted 06 May 2013

Publication Date:
11 June 2013 (online)

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Abstract

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.

Key words

diabetes - atrogenes - lysosomal/autophagic genes
 

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