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Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart
E. Dale Abel, … , Joanne S. Ingwall, Barbara B. Kahn
E. Dale Abel, … , Joanne S. Ingwall, Barbara B. Kahn
Published December 15, 1999
Citation Information: J Clin Invest. 1999;104(12):1703-1714. https://doi.org/10.1172/JCI7605.
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Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart

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Abstract

Glucose enters the heart via GLUT1 and GLUT4 glucose transporters. GLUT4-deficient mice develop striking cardiac hypertrophy and die prematurely. Whether their cardiac changes are caused primarily by GLUT4 deficiency in cardiomyocytes or by metabolic changes resulting from the absence of GLUT4 in skeletal muscle and adipose tissue is unclear. To determine the role of GLUT4 in the heart we used cre-loxP recombination to generate G4H–/– mice in which GLUT4 expression is abolished in the heart but is present in skeletal muscle and adipose tissue. Life span and serum concentrations of insulin, glucose, FFAs, lactate, and β-hydroxybutyrate were normal. Basal cardiac glucose transport and GLUT1 expression were both increased approximately 3-fold in G4H–/– mice, but insulin-stimulated glucose uptake was abolished. G4H–/– mice develop modest cardiac hypertrophy associated with increased myocyte size and induction of atrial natriuretic and brain natriuretic peptide gene expression in the ventricles. Myocardial fibrosis did not occur. Basal and isoproterenol-stimulated isovolumic contractile performance was preserved. Thus, selective ablation of GLUT4 in the heart initiates a series of events that results in compensated cardiac hypertrophy.

Authors

E. Dale Abel, Helen C. Kaulbach, Rong Tian, James C.A. Hopkins, John Duffy, Thomas Doetschman, Timo Minnemann, Mary-Ellen Boers, Ed Hadro, Corinna Oberste-Berghaus, William Quist, Bradford B. Lowell, Joanne S. Ingwall, Barbara B. Kahn

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Figure 2

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Glucose transporter expression. (a) Representative GLUT4 immunoblots of ...
Glucose transporter expression. (a) Representative GLUT4 immunoblots of postnuclear membranes of cardiac muscle obtained from female (F) and male (M) wild-type (+/+) and heart-selective GLUT4-ablated (G4H–/–; cre lox/lox) mice (left) and female mice of other genotypes: loxP homozygotes (lox/lox) and loxP heterozygotes (+/lox) without cre (right). Similar data exist for males. (b) Representative GLUT1 immunoblots of postnuclear membranes of cardiac muscle from female G4H–/– (cre lox/lox) mice, loxP homozygotic (lox/lox) mice, heterozygotic (+/lox) mice, and wild-type (+/+) mice. Similar data exist for males. (c) Densitometric analysis of GLUT1 immunoblots obtained from male and female G4H–/– mice and their wild-type controls (aged 18–21 weeks). GLUT1 densities are normalized to 1 for both males and females.Males: wild-type, n = 19; G4H–/–, n = 7. Females: wild-type, n = 6; G4H–/–, n = 6. *P < 0.001 vs. wild-type controls (2-tailed t test). (d) Representative GLUT4 immunoblots (from 5 mice of each genotype) demonstrating the preservation of GLUT4 expression in postnuclear membranes of skeletal muscle of G4H–/– (cre lox/lox) mice and normal expression of GLUT4 in loxP homozygotes without cre (lox/lox). (e) Representative GLUT4 immunoblots (from 17 mice of each genotype) of postnuclear membranes from white adipose tissue of wild-type (+/+), loxP homozygotic (lox/lox), and G4H–/– (cre lox/lox) male and female mice. Each panel represents a separate immunoblot. The third panel shows that there is no further change in GLUT4 content in G4H–/– (cre lox/lox) mice compared with loxP homozygous (lox/lox) mice.

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