Chronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling

Abstract

Boardman NT, Larsen TS, Severson DL, Essop MF, Aasum E. Chronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling. Am J Physiol Heart Circ Physiol 300: H1631-H1636, 2011. First published February 18, 2011 doi:10.1152/ajpheart.01190.2010The aim of the present study was to evaluate the underlying processes involved in the oxygen wasting induced by inotropic drugs and acute and chronic elevation of fatty acid (FA) supply, using unloaded perfused mouse hearts from normal and type 2 diabetic (db/db) mice. We found that an acute elevation of the FA supply in normal hearts, as well as a chronic (in vivo) exposure to elevated FA as in db/db hearts, increased myocardial oxygen consumption (MV O2unloaded) due to increased oxygen cost for basal metabolism and for excitation-contraction (EC) coupling. Isoproterenol stimulation, on top of a high FA supply, led to an additive increase in MV O2unloaded, because of a further increase in oxygen cost for EC coupling. In db/db hearts, the acute elevation of FA did not further increase MV O2. Since the elevation in the FA supply is accompanied by increased rates of myocardial FA oxidation, the present study compared MV O2 following increased FA load versus FA oxidation rate by exposing normal hearts to normal and high FA concentration (NF and HF, respectively) and to compounds that either stimulate (GW-610742) or inhibit [dichloroacetate (DCA)] FA oxidation. While HF and NF ϩ GW-610742 increased FA oxidation to the same extent, only HF increased MV O2unloaded. Although DCA counteracted the HF-induced increase in FA oxidation, DCA did not reduce MV O2unloaded. Thus, in normal hearts, acute FA-induced oxygen waste is 1) due to an increase in the oxygen cost for both basal metabolism and EC coupling and 2) not dependent on the myocardial FA oxidation rate per se, but on processes initiated by the presence of FAs. In diabetic hearts, chronic exposure to elevated circulating FAs leads to adaptations that afford protection against the detrimental effect of an acute FA load, suggesting different underlying mechanisms behind the increased MV O2 following acute and chronic FA load. cardiac efficiency; myocardial oxygen consumption; fatty acid oxidation; basal metabolism; isoproterenol SEVERAL PHYSIOLOGICAL AND pathophysiological conditions (including fasting, diabetes/obesity, postoperatively) are associated with elevated levels of circulating catecholamines and fatty acid (FA). Both conditions are known to increase myocardial oxygen consumption (MV O 2 ) more than would be expected by changes in cardiac work, leading to oxygen waste and thus decreased cardiac efficiency (27,38,44,50).Following chronic elevation of circulating lipids such as in diabetes and obesity, FA becomes the predominant fuel for ATP generation in the heart both due to elevated supply and transcriptional changes increasing the expression of genes associated with FA utilization (1, 4, 5). Altered myocardial substrate supply and decreased cardiac efficiency have b...

Mouse strain differences in metabolic fluxes and function of ex vivo working hearts

“…Our correlation data provide, however, some insight into linkages between cardiac metabolic flux and functional parameters, which need to be considered in data interpretation. Specifically, results from our correlation analyses concur and expand previously suggested associations between some specific fluxes and functional parameters, namely a positive association between glycolysis and functional parameters relevant to cardiac work (1,13,45) and the flux ratio relevant to exogenous FA oxidation (OLE/CS), MVO 2 , and myocardial perfusion (8,20,28,41). In addition, they are revealing some new ones, namely a positive correlation between flux ratios relevant to pyruvate oxidation (PDC/CS) or anaplerosis (PC/CS) and HR-related parameters.…”

“…Considering that cardiac metabolism is closely related to function (24,33,35,40), we aimed at evaluating linkages between strain-dependent variations in metabolic flux and functional parameters. Previous studies have reported positive association 1) between glycolysis and functional parameters relevant to myocardial work (1,13,45) and 2) LCFA oxidation and myocardial perfusion (8,20,28,41). Because these associations were not readily apparent from mean values reported for the various cardiac functional ( Fig.…”

Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2

“…In addition, as the relaxation factor is elevated and thus relaxation is slowed, one may also speculate that the prolonged crossbridge cycling may consume ATP and O 2 without a gain in stroke volume (26). Finally, it should also be noted that mechanical inefficiency would be further exacerbated in vivo due to the potential O 2 wasting effect after ␤-adrenergic stimulation (10,29,41).…”

“…Work-independent MV O2 was measured in the retrograde perfused unloaded heart (MV O2 unloaded). By electrically arresting these hearts (elevation of extracellular K ϩ concentration), we could also measure the O2 cost of basal metabolism (MV O2 BM), and the difference between MV O2 unloaded and MV O2 BM was used to obtain the O2 cost of ECC (MV O2 ECC) (2,9,10,15).…”

Cell Death and Heart Failure in Obesity: Role of Uncoupling Proteins

“…In addition, the increased UCP2 and UCP3 in heart, even if being associated with inefficiency of oxidative phosphorylation due to uncoupling, results in increased fatty acid oxidation as fuel utilization [92]. In several pathophysiological conditions such as insulin resistance, diabetes, and postischemia stressed heart, chronic exposure to elevated circulating FFAs leads to increased UCP3 as adaptations that afford protection against the detrimental effect of an acute FFA load [93, 94]. Indeed diabetic heart is characterized by UCP3 overexpression, increased fatty acid oxidation, increased myocardial oxygen consumption, and reduced cardiac efficiency [95].…”