Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy

Krüger, Martina; Babicz, Kamila; von Frieling-Salewsky, Marion; Linke, Wolfgang A.

doi:10.1016/j.yjmcc.2010.02.012

« Previous Next »Journal of Molecular and Cellular Cardiology
Volume 48, Issue 5 , Pages 910-916, May 2010

Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy

Martina Krüger
- Dept. of Cardiovascular Physiology, Ruhr University Bochum, D-44780 Bochum, Germany
- Corresponding authors. M. Krüger is to be contacted at Dept. of Cardiovascular Physiology, Ruhr University Bochum, MA 2/146, Universitätsstr. 150, D-44780 Bochum, Germany. Tel.: +49 234 3229104; fax: +49 234 3214040. W.A. Linke, Dept. of Cardiovascular Physiology, Ruhr University Bochum, MA 3/56, Universitätsstr. 150, D-44780 Bochum, Germany. Tel.: +49 234 3229100; fax: +49 234 3214040.
- Authors contributed equally to this study.
Kamila Babicz
- Dept. of Cardiovascular Physiology, Ruhr University Bochum, D-44780 Bochum, Germany
- Physiology and Biophysics Unit, University of Münster, D-48149 Münster, Germany
- Authors contributed equally to this study.
Marion von Frieling-Salewsky
- Dept. of Cardiovascular Physiology, Ruhr University Bochum, D-44780 Bochum, Germany
Wolfgang A. Linke
- Dept. of Cardiovascular Physiology, Ruhr University Bochum, D-44780 Bochum, Germany
- Corresponding authors. M. Krüger is to be contacted at Dept. of Cardiovascular Physiology, Ruhr University Bochum, MA 2/146, Universitätsstr. 150, D-44780 Bochum, Germany. Tel.: +49 234 3229104; fax: +49 234 3214040. W.A. Linke, Dept. of Cardiovascular Physiology, Ruhr University Bochum, MA 3/56, Universitätsstr. 150, D-44780 Bochum, Germany. Tel.: +49 234 3229100; fax: +49 234 3214040.

Received 30 October 2009; received in revised form 4 February 2010; accepted 15 February 2010. published online 24 February 2010.

Abstract

Isoform-switching of the giant elastic protein titin is a main mechanism for adjusting passive myocardial stiffness in perinatal heart development and chronic heart disease. Previous evidence suggested that thyroid-hormone signaling converging onto the phosphoinositol-3-kinase (PI3K)/AKT pathway regulates titin-isoform composition in developing cardiomyocytes. Here we hypothesized that insulin, another activator of PI3K/AKT, alters titin-isoform composition and titin-based stiffness. We also checked for insulin-induced changes in titin phosphorylation. In embryonic rat cardiomyocytes cultured in the presence of insulin for 7days, the mean proportion of the stiff N2B-titin isoform (M_w, 3000kDa) significantly increased from 53% in controls to 65% in insulin-treated cells, the remainder being the more compliant N2BA-isoforms (M_w, 3200–3700kDa). This insulin-dependent titin-isoform shift was blocked by PI3K-inhibitor, LY294002, suggesting that insulin controls the cardiac titin-isoform pattern by activating PI3K/AKT. Titin phosphorylation was substantially increased in insulin-treated compared to control cardiomyocytes. The impact of insulin-deficiency in vivo on titin-isoform expression, titin phosphorylation, and passive myocardial stiffness was studied in streptozotocin-treated (STZ) rats as a model of diabetes mellitus type-1. Within 5months, STZ rats developed cardiac hypertrophy and mild left ventricular fibrosis, concomitant with elevated glucose levels. The mean proportion of N2B-titin was slightly but significantly decreased from 86% in controls to 79% in STZ hearts. Titin phosphorylation levels remained unchanged. Mechanical measurements on skinned cardiac fibers showed only minor passive stiffness modifications in STZ myocardium. We conclude that insulin signaling regulates titin-isoform composition and titin phosphorylation in embryonic cardiomyocytes and could also contribute to altered diastolic function in diabetic cardiomyopathy.