Submitted on November 14, 2007
Accepted on January 24, 2008
ALTERATIONS IN CARBOHYDRATE METABOLISM AND ITS REGULATION IN PPAR ALPHA NULL MOUSE HEARTS
Roselle Gelinas1, Francois Labarthe2, Bertrand Bouchard3, Mc Duff Janie4, Charron Guy5, Martin E Young6, and Christine Des Rosiers3*
1 Montreal Heart Institute - Dept. of Nutrition, Montreal University, Montreal, Canada
2 CHRU de Tours, Universite Francois Rabelais, France
3 Montreal Heart Institute - Dept . of Nutrition, University of Montreal, Montreal, Canada
4 Montreal Heart Institute, Montreal, Canada; Montreal Heart Institute - Dept . of Nutrition, University of Montreal, Montreal, Canada
5 Montreal Heart Institute, Montreal, Canada
6 Department of Pediatrics, Baylor College of Medicine, Children's Nutrition Research Center, Houston, Texas, United States
* To whom correspondence should be addressed. E-mail: christine.des.rosiers{at}umontreal.ca.
While a shift from fatty acid (FA) to carbohydrates (CHO) is considered beneficial for the diseased heart, it is unclear why subjects with FA 
-oxidation defects are prone to cardiac decompensation under stress conditions. The present study investigated potential alterations in myocardial utilization of CHO for energy production and anaplerosis in 12-week-old peroxisomal proliferator-activating receptor-
(PPAR) null mice (a model of FA -oxidation defects). 13C-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 quantitative polymerase chain reaction was used to document the expression of selected metabolic genes. Compared to control C57BL/6 mice, isolated working hearts from PPAR 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, PPAR null hearts displayed also (i) a significantly greater contribution of exogenous lactate and glucose/glycogen (2-fold up) to endogenous pyruvate formation, while that of exogenous pyruvate remained unchanged; and (ii) marginal alterations in citric acid cycle-related parameters. The lactate production rate was the only measured parameter that was differently affected by preloads in control and PPAR 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.
