Glucose transporter 4-deficient hearts develop maladaptive hypertrophy in
response to physiological or pathological stresses.
Authors Wende AR, Kim J, Holland WL, Wayment BE, O'Neill BT, Tuinei J, Brahma MK, Pepin
ME, McCrory MA, Luptak I, Halade GV, Litwin SE, Abel ED
Submitted By E. Dale Abel on 1/5/2018
Status Published
Journal American journal of physiology. Heart and circulatory physiology
Year 2017
Date Published
Volume : Pages 313 : H1098 - H1108
PubMed Reference 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-? 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.NEW & NOTEWORTHY 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.

Investigators with authorship
E. Dale AbelUniversity of Iowa