Targeted GLUT-4 deficiency in the heart induces cardiomyocyte hypertrophy and impaired contractility linked with Ca(2+) and proton flux dysregulation.

Abstract

There is clinical evidence to suggest that impaired myocardial glucose uptake contributes to the pathogenesis of hypertrophic, insulin-resistant cardiomyopathy. The goal of this study was to determine whether cardiac deficiency of the insulin-sensitive glucose transporter, GLUT4, has deleterious effect on cardiomyocyte excitation-contraction coupling. Cre-Lox mouse models of cardiac GLUT4 knockdown (KD, 85% reduction) and knockout (KO, >95% reduction), which exhibit similar systemic hyperinsulinemic and hyperglycemic states, were investigated. The Ca(2+) current (I(Ca)) and Na(+)-Ca(2+) exchanger (NCX) fluxes, Na(+)-H(+) exchanger (NHE) activity, and contractile performance of GLUT4-deficient myocytes was examined using whole-cell patch-clamp, epifluorescence, and imaging techniques. GLUT4-KO exhibited significant cardiac enlargement characterized by cardiomyocyte hypertrophy (40% increase in cell area) and fibrosis. GLUT4-KO myocyte contractility was significantly diminished, with reduced mean maximum shortening (5.0+/-0.4% vs. 6.2+/-0.6%, 5 Hz). Maximal rates of shortening and relaxation were also reduced (20-25%), and latency was delayed. In GLUT4-KO myocytes, the I(Ca) density was decreased (-2.80+/-0.29 vs. -5.30+/-0.70 pA/pF), and mean I(NCX) was significantly increased in both outward (by 60%) and inward (by 100%) directions. GLUT4-KO expression levels of SERCA2 and RyR2 were reduced by approximately 50%. NHE-mediated H(+) flux in response to NH(4)Cl acid loading was markedly elevated GLUT4-KO myocytes, associated with doubled expression of NHE1. These findings demonstrate that, independent of systemic endocrinological disturbance, cardiac GLUT4 deficiency per se provides a lesion sufficient to induce profound alterations in cardiomyocyte Ca(2+) and pH homeostasis. Our investigation identifies the cardiac GLUT4 as a potential primary molecular therapeutic target in ameliorating the functional deficits associated with insulin-resistant cardiomyopathy.

• Authors: Andrea A Domenighetti, Vennetia R Danes, Claire L Curl, Jennifer M Favaloro, Joseph Proietto, Lea M D Delbridge
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 48 Issue 4 Pg. 663-72 (Apr 2010) ISSN: 1095-8584 [Electronic] England
• PMID: 19962383 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Chemical References

• Glucose Transporter Type 4
• Insulin
• Slc2a4 protein, mouse
• Calcium

Topics

• Animals
• Calcium (chemistry, metabolism)
• Glucose Transporter Type 4 (genetics, metabolism, physiology)
• Heart
• Hydrogen-Ion Concentration
• Hypertrophy (pathology)
• Insulin (metabolism)
• Male
• Mice
• Mice, Knockout
• Microscopy, Fluorescence (methods)
• Myocardium (pathology)
• Myocytes, Cardiac (metabolism, pathology)
• Patch-Clamp Techniques