Diabetes-Induced Cardiomyocyte Passive Stiffening Is Caused by Impaired Insulin-Dependent Titin Modification and Can Be Modulated by Neuregulin-1

Circulation Research
Anna-Eliane HopfMartina Krüger

Abstract

Increased titin-dependent cardiomyocyte tension is a hallmark of heart failure with preserved ejection fraction associated with type-2 diabetes mellitus. However, the insulin-related signaling pathways that modify titin-based cardiomyocyte tension, thereby contributing to modulation of diastolic function, are largely unknown. We aimed to determine how impaired insulin signaling affects titin expression and phosphorylation and thus increases passive cardiomyocyte tension, and whether metformin or neuregulin-1 (NRG-1) can correct disturbed titin modifications and increased titin-based stiffness. We used cardiac biopsies from human diabetic (n=23) and nondiabetic patients (n=19), cultured rat cardiomyocytes, left ventricular tissue from apolipoprotein E-deficient mice with streptozotocin-induced diabetes mellitus (n=12-22), and ZSF1 (obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid) rats (n=5-6) and analyzed insulin-dependent signaling pathways that modulate titin phosphorylation. Titin-based passive tension was measured using permeabilized cardiomyocytes. In human diabetic hearts, we detected titin hypophosphorylation at S4099 and hyperphosphorylation at S11878, suggesting altered activity of protein...Continue Reading

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Citations

Mar 13, 2019·International Journal of Molecular Sciences·Jovana Nikolajević StarčevićMišo Šabovič
Jun 7, 2019·Circulation Research·Ruth Williams, UNKNOWN Editors
Dec 21, 2018·The Journal of General Physiology·Rebecca E SlaterHenk L Granzier
Mar 2, 2019·Journal of Cardiovascular Translational Research·Shunchang LiIsmail Laher
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Jul 22, 2018·Circulation Research·Mei Methawasin, Henk Granzier
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Oct 13, 2020·Frontiers in Physiology·Mario SchubertKaomei Guan
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Feb 18, 2021·Cell Biology International·Zhengwei LiGuosheng Fu
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