Failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and glucose oxidation.
OBJECTIVE
To determine whether post-infarction LV dysfunction is due to low energy availability or inefficient energy utilization, we compared energy metabolism in normal and failing hearts. We also studied whether improved coupling of glycolysis and glucose oxidation by knockout of malonyl CoA decarboxylase (MCD-KO) would have beneficial effects on LV function and efficiency.


RESULTS
Male C57BL/6 mice were subjected to coronary artery ligation (CAL) or sham operation (SHAM) procedure. After 4 weeks and echocardiographic evaluation, hearts were perfused (working mode) to measure LV function and rates of energy metabolism. Similar protocols using MCD-KO mice and wild-type (WT) littermates were used to assess consequences of MCD deficiency. Relative to SHAM, CAL hearts had impaired LV function [lower % ejection fraction (%EF, 49%) and LV work (46%)]. CAL hearts had higher rates (expressed per LV work) of glycolysis, glucose oxidation, and proton production. LV work per ATP production from exogenous sources was lower in CAL hearts, indicative of inefficient exogenous energy substrate utilization. Fatty acid oxidation rates, ATP, creatine, and creatine phosphate contents were unaffected. Utilization of endogenous substrates, triacylglycerol and glycogen, was similar in CAL and SHAM hearts. MCD-KO CAL hearts had 31% higher %EF compared with that of WT-CAL, and lower rates of glycolysis, glucose oxidation, proton production, and ATP production, indicative of improved efficiency.


CONCLUSIONS
CAL hearts are inefficient in utilizing energy for mechanical function, possibly due to higher proton production arising from mismatched glycolysis and glucose oxidation. MCD deficiency lessens proton production, LV dysfunction, and inefficiency of exogenous energy substrate utilization.
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada T6G 2S2.
Waleed G T
WG
Masoud
John R
JR
Ussher
Wei
W
Wang
Jagdip S
JS
Jaswal
Cory S
CS
Wagg
Jason R
JR
Dyck
Craig A
CA
Lygate
Stefan
S
Neubauer
Alexander S
AS
Clanachan
Gary D
GD
Lopaschuk
D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism; D004734:Energy Metabolism; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D006334:Heart Function Tests; D066298:In Vitro Techniques; D008297:Male; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000150:complications*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000378:metabolism*; D020257:Ventricular Remodeling
D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase
Efficiency; Energy starvation; Energy substrate metabolism; Heart failure; Malonyl CoA decarboxylase