|Gelinas, Roselle -|
|Labarthe, Francois -|
|Bouchard, Bertrand -|
|Mc Duff, Janie -|
|Charron, Guy -|
|Young, Martin -|
|DE Rosiers, Christine -|
Submitted to: American Journal of Physiology - Heart and Circulatory Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: September 25, 2007
Publication Date: January 25, 2008
Citation: Gelinas, R., Labarthe, F., Bouchard, B., McDuff, J., Charron, G., Young, M.E., De Rosiers, C. 2008. Alterations in carbohydrate metabolism and its regulation in PPARalpha null mouse hearts. American Journal of Physiology - Heart and Circulatory Physiology. 294(4):H1571-H1580. Interpretive Summary: In order to pump blood around the body, the heart must burn fuels as a source of energy. Two major sources of energy for the heart are fatty acids and carbohydrates. The protein PPARa has been implicated as a key controller of heart energy metabolism. Mice were generated that do not possess the PPARa protein. Heart function and metabolism were investigated. The study shows that PPARa regulates not only fatty acid metabolism, but also carbohydrate metabolism. Changes in PPARa activity, and subsequent changes in heart metabolism, may contribute to contractile function problems observed in heart disease states.
Technical Abstract: 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.