Targeted GLUT-4 deficiency in the heart induces cardiomyocyte hypertrophy and impaired contractility linked with Ca2+ and proton flux dysregulation

Andrea A. Domenighetti, Vennetia R. Danes, Claire L. Curl, Jennifer M. Favaloro, Joseph Proietto, Lea M D Delbridge

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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 Ca2+ current (ICa) and Na+-Ca2+ 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 ICa density was decreased (- 2.80 ± 0.29 vs. - 5.30 ± 0.70 pA/pF), and mean INCX 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 NH4Cl 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)663-672
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Issue number4
StatePublished - Apr 2010


  • Calcium homeostasis
  • Cardiomyocyte
  • Excitation-contraction coupling
  • GLUT4 knockout
  • Myocardial insulin resistance
  • NCX
  • NHE
  • pH regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'Targeted GLUT-4 deficiency in the heart induces cardiomyocyte hypertrophy and impaired contractility linked with Ca2+ and proton flux dysregulation'. Together they form a unique fingerprint.

Cite this