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

Huggins, C.E., Domenighettia, A.A., Ritchie, M.E., Khalila, N., Favaloroc, J.M., Proiettoc, J., Smyth, G.K., Pepe, P. and Delbridge, L.M.D. 2008, Functional and metabolic remodelling in GLUT4-deficient hearts confers hyper-responsiveness to substrate intervention, Journal of molecular and cellular cardiology, vol. 44, no. 2, pp. 270-280, doi: 10.1016/j.yjmcc.2007.11.020.

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Title Functional and metabolic remodelling in GLUT4-deficient hearts confers hyper-responsiveness to substrate intervention
Author(s) Huggins, C.E.
Domenighettia, A.A.
Ritchie, M.E.
Khalila, N.
Favaloroc, J.M.
Proiettoc, J.
Smyth, G.K.
Pepe, P.
Delbridge, L.M.D.
Journal name Journal of molecular and cellular cardiology
Volume number 44
Issue number 2
Start page 270
End page 280
Publisher Academic Press
Place of publication London, England
Publication date 2008-02
ISSN 0022-2828
Keyword(s) hypertrophy
insulin resistance
GLUT4 transporter
metabolic remodelling
myocardial metabolism
gene expression profiling
Summary 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’.
Language eng
DOI 10.1016/j.yjmcc.2007.11.020
Field of Research 110201 Cardiology (incl Cardiovascular Diseases)
HERDC Research category C1.1 Refereed article in a scholarly journal
HERDC collection year 2008
Copyright notice ©2007, Elsevier Inc
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Document type: Journal Article
Collections: Faculty of Health
School of Exercise and Nutrition Sciences
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