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Functional and metabolic remodelling in GLUT4-deficient hearts confers hyper-responsiveness to substrate intervention

journal contribution
posted on 2008-02-01, 00:00 authored by Catherine Huggins, A Domenighettia, M Ritchie, N Khalila, J Favaloroc, J Proiettoc, G Smyth, P Pepe, L Delbridge
Impaired glucose uptake is associated with both cardiac hypertrophy and contractile dysfunction, but whether there are common underlying  mechanisms linking these conditions is yet to be determined. Using a ‘gene dose’ Cre-Lox GLUT4-deficient murine model, we examined the effect of suppressed glucose availability on global myocardial gene expression and glycolysis substrate bypass on the function of isolated perfused hearts. Performance of hearts from 22- to 60-week-old male GLUT4 knockout (KO, > 95% reduction in GLUT4), GLUT4 knockdown (KD, 85% reduction in cardiac GLUT4) and C57Bl/6 wild-type (WT) controls was measured ex vivo in Langendorff mode perfusion. DNA microarray was used to profile mRNA expression differences between GLUT4-KO and GLUT4-KD hearts. At 22 weeks, GLUT4-KO hearts exhibited cardiac hypertrophy and impaired contractile function ex vivo, characterized by a 40% decrease in developed pressure. At 60 weeks, dysfunction was accentuated in GLUT4-KO hearts and evident in GLUT4-KD hearts. Exogenous pyruvate (5 mM) restored systolic pressure to a level equivalent to WT (GLUT4-KO, 176.8 ± 13.2 mmHg vs. WT, 146.4 ± 9.56 mmHg) in 22-week-old GLUT4-KO hearts but not in 60-week-old GLUT4-KO hearts. In GLUT4-KO, DNA microarray analysis detected downregulation of a number of genes centrally involved in mitochondrial oxidation and upregulation of other genes indicative of a shift to cytosolic β-oxidation of long chain fatty acids. A direct link between cardiomyocyte GLUT4 deficiency, hypertrophy and contractile dysfunction is demonstrated. These data provide mechanistic insight into the myocardial metabolic adaptations associated with short and long-term insulin resistance and indicate a window of opportunity for substrate intervention and functional ‘rescue’.

History

Journal

Journal of molecular and cellular cardiology

Volume

44

Issue

2

Pagination

270 - 280

Publisher

Academic Press

Location

London, England

ISSN

0022-2828

eISSN

1095-8584

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2007, Elsevier Inc