Journal article
Glucose transporter 4-deficient hearts develop maladaptive hypertrophy in response to physiological or pathological stresses
American journal of physiology. Heart and circulatory physiology, Vol.313(6), pp.H1098-H1108
12/01/2017
DOI: 10.1152/ajpheart.00101.2017
PMCID: PMC5814656
PMID: 28822962
Abstract
Pathological cardiac hypertrophy may be associated with reduced expression of glucose transporter 4 (GLUT4) in contrast to exercise-induced cardiac hypertrophy, where GLUT4 levels are increased. However, mice with cardiac-specific deletion of GLUT4 (G4H
) have normal cardiac function in the unstressed state. This study tested the hypothesis that cardiac GLUT4 is required for myocardial adaptations to hemodynamic demands. G4H
and control littermates were subjected to either a pathological model of left ventricular pressure overload [transverse aortic constriction (TAC)] or a physiological model of endurance exercise (swim training). As predicted after TAC, G4H
mice developed significantly greater hypertrophy and more severe contractile dysfunction. Somewhat surprisingly, after exercise training, G4H
mice developed increased fibrosis and apoptosis that was associated with dephosphorylation of the prosurvival kinase Akt in concert with an increase in protein levels of the upstream phosphatase protein phosphatase 2A (PP2A). Exercise has been shown to decrease levels of ceramide; G4H
hearts failed to decrease myocardial ceramide in response to exercise. Furthermore, G4H
hearts have reduced levels of the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1, lower carnitine palmitoyl-transferase activity, and reduced hydroxyacyl-CoA dehydrogenase activity. These basal changes may also contribute to the impaired ability of G4H
hearts to adapt to hemodynamic stresses. In conclusion, GLUT4 is required for the maintenance of cardiac structure and function in response to physiological or pathological processes that increase energy demands, in part through secondary changes in mitochondrial metabolism and cellular stress survival pathways such as Akt.
Glucose transporter 4 (GLUT4) is required for myocardial adaptations to exercise, and its absence accelerates heart dysfunction after pressure overload. The requirement for GLUT4 may extend beyond glucose uptake to include defects in mitochondrial metabolism and survival signaling pathways that develop in its absence. Therefore, GLUT4 is critical for responses to hemodynamic stresses.
Details
- Title: Subtitle
- Glucose transporter 4-deficient hearts develop maladaptive hypertrophy in response to physiological or pathological stresses
- Creators
- Adam R Wende - Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AlabamaJaetaek Kim - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UtahWilliam L Holland - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UtahBenjamin E Wayment - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UtahBrian T O'Neill - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IowaJoseph Tuinei - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UtahManoja K Brahma - Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AlabamaMark E Pepin - Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AlabamaMark A McCrory - Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AlabamaIvan Luptak - Division of Cardiology, Boston University School of Medicine, Boston, MassachusettsGanesh V Halade - Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; andSheldon E Litwin - Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UtahE Dale Abel - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Heart and circulatory physiology, Vol.313(6), pp.H1098-H1108
- Publisher
- United States
- DOI
- 10.1152/ajpheart.00101.2017
- PMID
- 28822962
- PMCID
- PMC5814656
- ISSN
- 0363-6135
- eISSN
- 1522-1539
- Grant note
- R00 HL111322 / NHLBI NIH HHS R01 DK092065 / NIDDK NIH HHS U01 HL087947 / NHLBI NIH HHS
- Language
- English
- Date published
- 12/01/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984025295002771
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