Real-time assessment of Krebs cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy - PubMed (original) (raw)
Real-time assessment of Krebs cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy
Marie A Schroeder et al. FASEB J. 2009 Aug.
Abstract
The Krebs cycle plays a fundamental role in cardiac energy production and is often implicated in the energetic imbalance characteristic of heart disease. In this study, we measured Krebs cycle flux in real time in perfused rat hearts using hyperpolarized magnetic resonance spectroscopy (MRS). [2-(13)C]Pyruvate was hyperpolarized and infused into isolated perfused hearts in both healthy and postischemic metabolic states. We followed the enzymatic conversion of pyruvate to lactate, acetylcarnitine, citrate, and glutamate with 1 s temporal resolution. The appearance of (13)C-labeled glutamate was delayed compared with that of other metabolites, indicating that Krebs cycle flux can be measured directly. The production of (13)C-labeled citrate and glutamate was decreased postischemia, as opposed to lactate, which was significantly elevated. These results showed that the control and fluxes of the Krebs cycle in heart disease can be studied using hyperpolarized [2-(13)C]pyruvate.
Figures
Figure 1.
A representative recording of cardiac function throughout the perfusion protocol, showing developed pressure, heart rate and rate pressure product. Left panel: effects of hyperpolarized pyruvate infusion during the first 2 min of MR data acquisition. Right panel: ischemia and 5 min of postischemic recovery.
Figure 2.
Example stacked spectra acquired in the first 60 s following [2-13C]pyruvate infusion into a perfused rat heart. [2-13C]Pyruvate was observed at 207.8 ppm. Peaks 1, 2, and 3 represent the metabolic products [5-13C]glutamate (183.7 ppm), [1-13C]citrate (181.0 ppm), and [1-13C]acetylcarnitine (175.2 ppm), respectively. [1-13C]Pyruvate derived from natural abundance 13C was seen as a quartet at 172.8 ppm (peak 4, left inset). [2-13C]Pyruvate hydrate, which is in chemical equilibrium with pyruvate, was detected at 96.5 ppm (peak 5, right inset). Impurities in the [2-13C]pyruvic acid preparation were observed at ∼149 and 89 ppm (peak 6, right inset). [2-13C]Lactate and [2-13C]alanine could also be observed (peaks 7 and 8, respectively).
Figure 3.
Annotated 2-D heteronuclear multiple bond correlations. The y axis shows 13C chemical shifts, and the x axis shows 1H chemical shifts. Shaded regions within the plot indicate nuclei for which coupling between 1H and 13C resonances had been detected. Peaks were assigned based on both 1H and 13C resonances. Inset: spectral region corresponding with previously unassigned hyperpolarized 13C peaks detected in the isolated perfused heart.
Figure 4.
Progression of the metabolic products of [2-13C]pyruvate, for healthy perfused hearts (_n_=6). Data were acquired with a 1-s temporal resolution, using a 30° RF pulse.
Figure 5.
Summary of the metabolic fate of infused [2-13C]pyruvate along with the measured parameters of the observed metabolites.
Figure 6.
Comparison of the average metabolic time courses for lactate, acetylcarnitine, citrate, and glutamate in both the healthy and postischemic hearts. Image shows a significant elevation in the lactate signal following a 10 min ischemic period, along with a significant reduction in the citrate and glutamate signals.
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