Long-term effects of increased glucose entry on mouse hearts during normal aging and ischemic stress.
BACKGROUND
A shift of substrate preference toward glucose in the heart is considered a reversion to fetal metabolic profile, but its role in the pathogenesis of cardiac diseases is incompletely understood.


RESULTS
We performed a 2-year follow-up study in transgenic mice with sustained high glucose uptake and utilization in the heart by cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (GLUT1-TG). Compared with wild-type litter mates, the GLUT1-TG mice showed a normal survival rate and unaltered contractile function of the heart monitored by serial echocardiography and by pressure-volume studies in isolated perfused hearts in the 2-year period. Furthermore, when hearts were subjected to ischemia-reperfusion, cardiac function of young and old GLUT1-TG recovered to the same level (86% and 83%, respectively) and exceeded that of both young and old wild-type hearts (52% and 35%, respectively; P<0.05). Nuclear magnetic resonance spectroscopic measurements with 31P showed delayed ATP depletion, reduced acidosis during ischemia, and improved recovery of high-energy phosphate content in old GLUT1-TG hearts (P<0.05 versus old wild-type). During reperfusion, glucose oxidation was 3-fold higher and fatty acid oxidation was 45% lower in old GLUT1-TG hearts compared with old wild-type (P<0.05), which suggests that the deleterious effects of excessive fatty acid oxidation during reperfusion was prevented in old GLUT1-TG hearts.


CONCLUSIONS
We have demonstrated that a normal heart is able to adapt to long-term increases in basal glucose entry into cardiomyocytes without development of glucotoxicity. Furthermore, life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against aging-associated increase of susceptibility to ischemic injury.
Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Ivan
I
Luptak
Jie
J
Yan
Lei
L
Cui
Mohit
M
Jain
Ronglih
R
Liao
Rong
R
Tian
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002247:Carbon Isotopes; D004452:Echocardiography; D004734:Energy Metabolism / Q000502:physiology; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D050261:Glycogenolysis / Q000502:physiology; D006019:Glycolysis / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000401:mortality; D009206:Myocardium / Q000378:metabolism*; D010759:Phosphorus Isotopes; D011877:Radionuclide Imaging
D001786:Blood Glucose; D002247:Carbon Isotopes; D051272:Glucose Transporter Type 1; D010759:Phosphorus Isotopes; C495678:Slc2a1 protein, mouse; D000255:Adenosine Triphosphate