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Alterations in carbohydrate metabolism and its regulation in PPAR null mouse hearts

¹Department of Nutrition, Université de Montréal and Montreal Heart Institute, Montreal, Quebec, Canada; ²Centre Hospitalier Régional et Universitaire de Tours, Université François Rabelais, Institut National de la Santé et de la Recherche Médicale E211, Tours, France; and ³Department of Pediatrics, Baylor College of Medicine, Houston, Texas

Submitted 14 November 2007 ; accepted in final form 24 January 2008

Although a shift from fatty acids (FAs) to carbohydrates (CHOs) is considered beneficial for the diseased heart, it is unclear why subjects with FA β-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- (PPAR) null mice (a model of FA β-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 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 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 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.

isolated working mouse heart perfusion; citric acid cycle; ¹³C isotopomer analysis; glycolysis; ATP-citrate lyase; peroxisome proliferator-activated receptor-