Persistent overexpression of phosphoglycerate mutase, a glycolytic enzyme, modifies energy metabolism and reduces stress resistance of heart in mice.
BACKGROUND
Heart failure is associated with changes in cardiac energy metabolism. Glucose metabolism in particular is thought to be important in the pathogenesis of heart failure. We examined the effects of persistent overexpression of phosphoglycerate mutase 2 (Pgam2), a glycolytic enzyme, on cardiac energy metabolism and function.


RESULTS
Transgenic mice constitutively overexpressing Pgam2 in a heart-specific manner were generated, and cardiac energy metabolism and function were analyzed. Cardiac function at rest was normal. The uptake of analogs of glucose or fatty acids and the phosphocreatine/βATP ratio at rest were normal. A comprehensive metabolomic analysis revealed an increase in the levels of a few metabolites immediately upstream and downstream of Pgam2 in the glycolytic pathway, whereas the levels of metabolites in the initial few steps of glycolysis and lactate remained unchanged. The levels of metabolites in the tricarboxylic acid (TCA) cycle were altered. The capacity for respiration by isolated mitochondria in vitro was decreased, and that for the generation of reactive oxygen species (ROS) in vitro was increased. Impaired cardiac function was observed in response to dobutamine. Mice developed systolic dysfunction upon pressure overload.


CONCLUSIONS
Constitutive overexpression of Pgam2 modified energy metabolism and reduced stress resistance of heart in mice.
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Junji
J
Okuda
Shinnichiro
S
Niizuma
Tetsuo
T
Shioi
Takao
T
Kato
Yasutaka
Y
Inuzuka
Tsuneaki
T
Kawashima
Yodo
Y
Tamaki
Akira
A
Kawamoto
Yohei
Y
Tanada
Yoshitaka
Y
Iwanaga
Michiko
M
Narazaki
Tetsuya
T
Matsuda
Souichi
S
Adachi
Tomoyoshi
T
Soga
Genzou
G
Takemura
Hiroshi
H
Kondoh
Toru
T
Kita
Takeshi
T
Kimura
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D004452:Echocardiography; D004734:Energy Metabolism / Q000235:genetics*; D004789:Enzyme Activation; D005355:Fibrosis; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D010736:Phosphoglycerate Mutase / Q000235:genetics* / Q000378:metabolism; D011877:Radionuclide Imaging; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*
D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D004280:Dobutamine; D010736:Phosphoglycerate Mutase; D005947:Glucose