Alterations in carbohydrate metabolism and its regulation in PPARalpha null mouse hearts.
Although a shift from fatty acids (FAs) to carbohydrates (CHOs) is considered beneficial for the diseased heart, it is unclear why subjects with FA beta-oxidation defects are prone to cardiac decompensation under stress conditions. The present study investigated potential alterations in the myocardial utilization of CHOs for energy production and anaplerosis in 12-wk-old peroxisome proliferator-activating receptor-alpha (PPARalpha) null mice (a model of FA beta-oxidation defects). Carbon-13 methodology was used to assess substrate flux through energy-yielding pathways in hearts perfused ex vivo at two workloads with a physiological substrate mixture mimicking the fed state, and real-time RT-quantitative polymerase chain reaction was used to document the expression of selected metabolic genes. When compared with that from control C57BL/6 mice, isolated working hearts from PPARalpha null mice displayed an impaired capacity to withstand a rise in preload (mimicking an increased venous return as it occurs during exercise) as reflected by a 20% decline in the aortic flow rate. At the metabolic level, beyond the expected shift from FA (5-fold down) to CHO (1.5-fold up; P < 0.001) at both preloads, PPARalpha null hearts also displayed 1) a significantly greater contribution of exogenous lactate and glucose and/or glycogen (2-fold up) to endogenous pyruvate formation, whereas that of exogenous pyruvate remained unchanged and 2) marginal alterations in citric acid cycle-related parameters. The lactate production rate was the only measured parameter that was affected differently by preloads in control and PPARalpha null mouse hearts, suggesting a restricted reserve for the latter hearts to enhance glycolysis when the energy demand is increased. Alterations in the expression of some glycolysis-related genes suggest potential mechanisms involved in this defective CHO metabolism. Collectively, our data highlight the importance of metabolic alterations in CHO metabolism associated with FA oxidation defects as a factor that may predispose the heart to decompensation under stress conditions even in the fed state.
Gélinas
Roselle
R
Montreal Heart Inst. Research Center, 5350, Montreal, Quebec, Canada H1T 1C8.
Labarthe
François
F
Bouchard
Bertrand
B
Mc Duff
Janie
J
Charron
Guy
G
Young
Martin E
ME
Des Rosiers
Christine
C
D000818:Animals; D050260:Carbohydrate Metabolism / Q000235:genetics; D002247:Carbon Isotopes; D002952:Citric Acid Cycle; D004734:Energy Metabolism / Q000235:genetics; D005215:Fasting / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005082:Physical Exertion; D019518:Postprandial Period; D019289:Pyruvic Acid / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D002247:Carbon Isotopes; D005227:Fatty Acids; D047493:PPAR alpha; D012333:RNA, Messenger; D019344:Lactic Acid; D019289:Pyruvic Acid; D006003:Glycogen; D005947:Glucose