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CELLULAR METABOLISM
1Program in Integrative Cardiac Metabolism, 2Center for Cardiovascular Research, University of Illinois, College of Medicine, Chicago, Illinois; and 3Department of Pediatrics, University of Iowa, College of Medicine, Iowa City, Iowa
Submitted 15 November 2006 ; accepted in final form 11 January 2007
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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malate-aspartate shuttle; redox state; hypertrophy
We have recently demonstrated that the neonatal heart, which is more glycolytically active than adult heart, adjusts to a relatively high level of glycolytic NADH production through elevated transfer rate of these cytosolic-reducing equivalents into mitochondria via malate-aspartate shuttle flux (7, 15). In that previous study, we observed that the increased malate-aspartate shuttle activity in the neonatal heart is supported by a relatively high level of expression of the shuttle protein, oxoglutarate-malate carrier (OMC) protein. As the developing heart reduces reliance on glucose metabolism during the shift to the adult metabolic profile of increased fatty acid oxidation, the myocardium reduces expression of both the malate-aspartate shuttle and glycerophosphate shuttle proteins, with essential elimination of the glycerophosphate shuttle (7, 26). Consequently, the malate-aspartate shuttle proteins eventually provide the predominant form of reducing equivalent transfer in adult myocardium, albeit at a reduced capacity from the neonatal stage. Indeed, in the adult heart, both flux through OMC and expression of the protein are reduced to approximately one-third of those seen in the neonatal heart (7). With the potential for the hypertrophic stimulus to initiate a reversion to neonatal metabolism, this study addresses the hypothesis that the hypertrophic heart, in shifting toward increased glucose metabolism, must adapt to the NADH/NAD+ balance of the cytosol through adjustments in OMC activity and/or expression.
To address this hypothesis, we employed dynamic-mode 13C NMR to measure flux across the primary transporter protein involved in the transfer of cytosolic NADH into the mitochondrial matrix, OMC, in pressure-loaded rat hearts (7, 18, 30). Our objectives were to 1) determine adaptive changes in flux across OMC and OMC protein expression in response to the hypertrophic stimulus of pressure overload, and 2) to examine OMC activity and expression in hearts at the point of development of compensatory hypertrophy. This study is the first to investigate altered mitochondrial transport processes in intact hypertrophic hearts and, importantly, demonstrate the distinctions between metabolic regulation and gene expression in the adaptive responses to a disease process.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Isolated perfused rat heart. Animals were heparinized (500 U/100 g ip) and anesthetized with pentobarbital sodium (100 mg/kg ip). Hearts were excised and perfused in retrograde fashion at 100-cm hydrostatic pressure, as previously described, with modified Krebs-Henseleit buffer composed of (in mM) 116 NaCl, 4 KCl, 1.5 CaCl2, 1.2 MgSO4, and 1.2 NaH2PO4, equilibrated with 95% O2-5% CO2 (7, 18, 30). A water-filled latex balloon was fitted into the left ventricle for hemodynamic recordings (PowerLab; ADInstruments, Colorado Springs, CO). The balloon was inflated with water to create a diastolic pressure of 5–10 mmHg. Left ventricular developed pressure and heart rate were continuously recorded. Rate-pressure product was calculated as the product of heart rate and developed pressure. The temperature of the hearts was continuously maintained at 37°C.
Experimental protocols. At the start of each protocol, the perfusate supply was switched to a 0.5-liter reservoir of buffer containing 2.0 mM unlabeled butyrate and 5 mM glucose for 10 min to ensure metabolic equilibrium and for collection of background signals of naturally abundant 13C (1.1%). During this period, a 31P spectrum was also acquired from each heart. The perfusate was then switched to a 1-liter supply of 13C-enriched buffer containing 2.0 mM [2,4-13C2]butyrate (Isotec, Miamisburg, OH) plus 5 mM unlabeled glucose. Sequential 13C NMR spectra began immediately upon delivery of 13C-enriched buffer over 35 min (7, 18, 30). The heart was rapidly frozen in liquid nitrogen-cooled tongs for in vitro analysis.
Butyrate is a short-chain fatty acid that undergoes 
-oxidation in cardiac mitochondria. Although not a physiological substrate, butyrate supports normal cardiac energetics and function and enables NMR measurements of metabolic flux in the intact beating heart (11, 13, 19, 29, 30). Prior studies on OMC activity in the neonatal heart have employed butyrate to match OMC expression to activity (7). Therefore, 13C-enriched butyrate was used as a probe of oxidative activity in the heart, enabling this protocol to focus on adjustments in OMC activity in the hypertrophied heart, without the potentially confounding variables associated with changes in long-chain fatty acid entry into oxidative metabolism via the expression and activity of carnitine palmitoyl transferase I.
Four experimental groups of hearts were studied: 1) 2 wk pressure overload (n = 6); 2) age-matched, 2-wk post operative shams (n = 6); 3) 10-wk pressure overload (n = 8); and 4) age-matched, 10-wk postoperative shams (n = 7).
These protocols were mirrored using additional hearts perfused with 2 mM unlabeled butyrate plus 5 mM [1,6-13C2]glucose to discern potential differences in the utilization of exogenous glucose vs. unlabeled, endogenous carbohydrate. Hearts were freeze clamped after 30 min and analyzed for the extent of glucose metabolism in the following groups: 1) 2-wk pressure overload (n = 5); 2) age-matched, 2-wk postoperative shams (n = 5); 3) 10 wk pressure overload (n = 6); 4) age-matched, 10-wk postoperative shams (n = 5).
NMR measurements. NMR parameters required for acquisition of 31P and 13C NMR spectra from isolated hearts are as previously reported (7, 11, 18, 19, 30). Perfused hearts were positioned in a 20-mm broadband probe in a 9.4-T/89-mm vertical-bore superconducting NMR magnet. 13C spectra were then acquired with bilevel broadband decoupling and subtracted from naturally abundant endogenous 13C signal. 31P spectra were acquired over a 2-min time period.
High-resolution 13C and 1H NMR spectra of perchloric acid extracts reconstituted in 0.5 ml 2H2O were obtained with a 5-mm probe placed in a Bruker 14-T magnet as previously reported (13, 29). The multiplet structures of the glutamate carbon signals allowed the fraction of [2-13C]-labeled acetyl-CoA entering the tricarboxylic acid (TCA) cycle to be calculated (10, 16). 1H NMR spectra and UV spectrophotometric assay allowed determination of the glycolytic production of alanine and lactate.
Kinetic modeling of 13C labeling of glutamate. Kinetic analysis of the 13C enrichment curves for the 4- and 2-carbon positions of glutamate was performed by least-squares fitting curves to a well-established model (14, 29, 31). As shown in Fig. 1, label from [2,4-13C2]butyrate enters the TCA cycle as [2-13C]acetyl-CoA. Oxoglutarate is first labeled at the C4 position and then with equal probability at the C2 and C3 positions on the second turn of the TCA cycle. The interconversion of mitochondrial oxoglutarate with the NMR-detectable pool of cytosolic glutamate is dominated by the rate-determining exchange of oxoglutarate across the mitochondrial membrane via OMC. Kinetic analysis of isotope data provided flux through the TCA cycle and through OMC (F1), which dominates the interconversion rate of oxoglutarate and glutamate (7, 14, 29, 30, 31).
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Statistical comparisons. Results are reported as means ± SD unless otherwise indicated. Comparison of mean values was performed using ANOVA, followed by a Newman-Keuls post hoc test. Functional measurements over time were compared using repeated-measures ANOVA. Differences in mean values were considered significant at a probability level of <5%.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The rate-pressure product was similar in all four experimental groups and did not vary significantly throughout the perfusion protocol. Rate-pressure product values (beats·min–1·mmHg) at the midpoint of the protocol were as follows: 2-wk sham = 29,778 ± 7,804; 2-wk banded = 28,843 ± 6,238; 10-wk sham = 26,173 ± 7,798; and 10-wk banded = 22,323 ± 3,829 (means ± SD). The pressure-overloaded hearts at both 2 and 10 wk showed no significant functional deficiency compared with the corresponding sham-operated hearts. As hearts in the 10-wk group had no evidence of hemodynamic decompensation or failure, the functional similarities between the pressure-overloaded hearts and the sham-operated hearts are to be expected.
Correspondingly, oxygen consumption was similar in all groups: 2-wk sham = 22.0 ± 4.3 (µmol·g–1·min–1; 2-wk banded = 24.1 ± 5.2; 10-wk sham = 23.8 ± 4.8; and 10-wk banded = 19.3 ± 3.4. Consistent with previous reports, banded hearts at 10 wk of pressure overload displayed reduced energy potential, as indexed by the ratio of phosphocreatine to ATP (4, 12): 2-wk sham = 1.91 ± 0.25 vs. 2-wk banded = 1.59 ± 0.39 (not significant; NS); and 10-wk sham = 1.98 ± 0.29 vs. 10-wk banded = 1.62 ± 0.27 (P < 0.05).
Metabolic flux measurements and OMC activity. Representative 13C NMR spectra of the intact beating hearts, oxidizing [2,4-13C2]butyrate, are shown in Fig. 2 with 13C enrichment curves of the glutamate carbon positions, as described in MATERIALS AND METHODS and as shown in Fig. 3. Isotopic steady state within the glutamate pool was reached within the first 20 min of the enrichment protocol as previously observed (7, 19, 29). Measured input parameters for the analysis of glutamate enrichment kinetics are shown in Table 1. Glutamate content in the myocardium of hearts at 2 wk of pressure overload was increased, as expected due to an increase in OMC activity (18).
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As expected from the inhibitory effects of short-chain fatty acid on carbohydrate oxidation, very little glucose was oxidized in the presence of butyrate as an oxidizable substrate (5, 8, 27, 30). Interestingly, though, nonoxidative glycolysis as indicated by an increase in glycolytic end production formation (lactate and alanine), particularly that of lactate, was higher in the 2-wk banded group than in the corresponding 2-wk sham group (Table 1). Indeed, the 2-wk banded group was the only set displaying elevated lactate content (P < 0.01). This finding is consistent with increased drive of the malate-aspartate shuttle via elevated cytosolic redox state in the 2-wk banded group, as linked to the observed increased flux through OMC (23, 30). While a general increase in glycolysis was evident in the pressure-overloaded hearts, no distinctions were evident in the fate of the exogenous, enriched glucose vs. the endogenous, unlabeled glucose.
OMC expression in pressure-overloaded hearts. Despite increased metabolite exchange via OMC in hearts at 2 wk of pressure overload relative to sham hearts, OMC protein expression remained unchanged (Fig. 5). Hearts subjected to 10 wk of pressure overload showed mean OMC protein to be slightly elevated (30%) over sham hearts, although not significantly. These results are similar to the findings reported by Rupert et al. (22). However, previous studies were not able to evaluate flux through this transporter protein in the hypertrophied heart.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The 31P NMR data showing depressed an energetic profile in hearts of these aortic banded animals is consistent with previous reports of cardiac energetics in hypertrophy (4, 17). The phosphocreatine-to-ATP ratio was equally perturbed at both 2 and 10 wk of pressure overload and, as a general characteristic of the hypertrophic heart, did not correlate to OMC flux.
In cardiac hypertrophy, a phenotypic reprogramming occurs in the heart, such that genes that are normally expressed during development are recapitulated, including gene-encoding metabolic enzymes (21). Metabolic studies on hypertrophied hearts have clearly documented an increase in glycolytic energy production compared with that of the normal heart (9, 24). This shift is consistent with reversion to fetal gene expression program that was initially characterized for genes encoding myocyte contractile proteins (20, 25). While we have observed a clear increase in the activity of OMC in the pressure-overloaded rat heart, protein levels did not revert to the fetal expression pattern that would present significantly elevated OMC expression either upon the onset of the hypertrophic stimulus or at the point of compensatory hypertrophy. The sole drive for increased OMC flux then appears to be due to increased glycolytic activity, as shown increased lactate and alanine content in the 2-wk banded group.
Interestingly, the net appearance of NADH in the mitochondrial matrix, which occurred through the sum of both NADH production via TCA cycle flux and NADH transfer from the cytosol, were well matched in both sham and banded heart groups at 2 wk to support similar levels of contractile function. The general production of 3 NADH per single cycle of the TCA pathway indicates that the mean TCA cycle flux for sham hearts, of 9.8 µmol·min–1·g–1, produced 29.4 NADH µmol·min–1·g–1, whereas the mean TCA cycle flux of 8.3 µmol·min–1·g–1 in the banded group produced 24.9 NADH·min–1·g–1. However, the different contributions of NADH influx into the mitochondria via OMC activity brings the mean values of NADH generation in the mitochondria to very similar levels of 33.1 NADH·min–1·g–1 in the sham group and 34.5 NADH·min–1·g–1 in the 2-wk banded group. Thus the similarity in total NADH contributing to oxidative energy synthesis in the mitochondria accounts for the observed similarities in oxygen consumption observed in both the sham and pressure-overloaded hearts. The importance of this finding is that in the 2-wk pressure-overloaded heart, glycolytic production of NADH contributed significantly to maintaining normal rates of energy synthesis and this contribution diminished with the eventual development of compensatory hypertrophy.
Indeed, although statistical comparison does not indicate significance, the trend for OMC protein content in compensated hypertrophic myocardium was an increase by one-third the amount of protein in the sham hearts. In this case, the relative flux through OMC per quantity of OMC protein in the heart remains elevated even in the 10-wk banded animals. Therefore, the large increase in OMC flux before the development of compensatory hypertrophy represents an adjustment in metabolic regulation in response to the hypertrophic stimulus.
The elevated flux through OMC then becomes an important adaptive mechanism that serves to maintain cytosolic redox state (NADH/NAD+) in the presence of a previously reported mismatch between the elevated glycolytic activity of the hypertrophied and the relatively unchanged oxidation of glycolytic end products (9, 24). Importantly, these observations of increased OMC flux and glycolytic metabolism occurred in hearts subjected to the stress of pressure overload, before the development of hypertrophy. Although the present study focuses not on glucose metabolism, but rather on the activity of the key transporter for cytosolic reducing equivalents OMC, our data on the 13C enrichment of acetyl CoA (Table 1) demonstrate no differences between sham hearts and pressure-overloaded hearts in the relative contributions to oxidative metabolism between butyrate and glucose. Therefore, no increase in the oxidation of glycolytic end products was observed in this study of pressure-overloaded hearts, supporting the previously reported findings (9, 24).
Although the aim of this study was the measurement of flux through OMC that precluded measurements of glycolytic flux, these new data build on the previously published reports of changes in the intermediary metabolism of the hypertrophied rat heart (9, 17, 22, 24). The findings of this study indicate that shortly after imposition of the hypertrophic stimulus of pressure overload, flux through OMC is dramatically increased in the heart, as reducing equivalent transfer from the glycolytically produced, cytosolic NADH is accommodated by the malate-aspartate shuttle for oxidative metabolism in the mitochondria. Evidence is shown here for a transient spike in the activity of nonoxidative glycolysis that is a likely culprit for driving OMC. As the early elevation of glycolysis has been observed in the isolated heart, it represents and intrinsic change in myocardial metabolism.
Interestingly, once compensation occurs after 10 wk of pressure overload, the flux through OMC returns toward baseline levels, similar to those observed in the sham hearts. Together, data from both the 2- and 10-wk time points of pressure overload indicate that development of compensatory hypertrophy at least partially restores the redox state balance (NADH/NAD+) between the cytosol and mitochondria, which is initially disrupted during the initial metabolic response to pressure overload.
Our further analysis of OMC content in pressure-overloaded hearts indicates that the changes in OMC flux that were observed in this study are the direct result of metabolic regulation and not a change in the expression of the enzyme. While we have observed a clear increase in the activity of OMC in the pressure-overloaded heart (at 2 wk), protein levels did not revert to the fetal expression pattern (7). An earlier study, by Rupert et al. (22), also demonstrated that protein levels of OMC do not increase in the rat heart following pressure overload produced by banding of the abdominal aorta.
Nonetheless, the lack of change in OMC content in response to the hypertrophic stimulus belies the altered activity of this carrier protein and the changes in OMC activity that occur in parallel with the development of compensatory cardiac hypertrophy. The results show, in general, that the metabolic responses to pressure overload in the heart are not static. Rather, the initial spike in OMC activity and eventual moderation toward baseline activity in hypertrophic hearts suggests that meeting the metabolic demands of cardiac function is a dynamic process over the course of the pathophysiology that ultimate leads toward decompensated hypertrophy and heart failure. Indeed, this process clearly adapts to the current pathophysiological state and may induce subsequent adaptive responses that do not involve distinct changes in enzyme expression. The larger implication of the work is that in vitro assays that rely primarily on enzyme content or enzyme kinetics, in the absence of the metabolic driving forces provided by the function of the intact ventricle, do not reflect the regulatory control of metabolic processes in the cardiomyocyte.
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GRANTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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, 4-Carbon of glutamate; 
, 2-carbon of glutamate. Top, sham-operated hearts at 2 wk (Sham). Bottom, pressure-overloaded hearts at 2 wk (Hyp). Note the relative differences between 13C enrichment at the 2-carbon position of glutamate vs. that of the 4-carbon between the sham-operated hearts (top) and the pressure-overloaded hearts (bottom).
