Abstract
BackgroundAlterations in cardiac metabolism accompany many diseases of the heart. The advent of cardiac hyperpolarized magnetic resonance spectroscopy (MRS), via dynamic nuclear polarization (DNP), has enabled a greater understanding of the in vivo metabolic changes that occur as a consequence of myocardial infarction, hypertrophy and diabetes. However, all cardiac studies performed to date have focused on rats and larger animals, whereas more information could be gained through the study of transgenic mouse models of heart disease. Translation from the rat to the mouse is challenging, due in part to the reduced heart size (1/10th) and the increased heart rate (50%) in the mouse compared to the rat.Methods and ResultsIn this study, we have investigated the in vivo metabolism of [1-13C]pyruvate in the mouse heart. To demonstrate the sensitivity of the method to detect alterations in pyruvate dehydrogenase (PDH) flux, two well characterised methods of PDH modulation were performed; overnight fasting and infusion of sodium dichloroacetate (DCA). Fasting resulted in an 85% reduction in PDH flux, whilst DCA infusion increased PDH flux by 123%. A comparison of three commonly used control mouse strains was performed revealing significant metabolic differences between strains.ConclusionsWe have successfully demonstrated a hyperpolarized DNP protocol to investigate in vivo alterations within the diseased mouse heart. This technique offers a significant advantage over existing in vitro techniques as it reduces animal numbers and decreases biological variability. Thus [1-13C]pyruvate can be used to provide an in vivo cardiac metabolic profile of transgenic mice.
Highlights
Alterations in cardiac metabolism accompany many diseases of the heart
Acquisition of [1-13C]pyruvate in the in vivo mouse heart A typical set of spectra from a fed control mouse is shown in Figure 2 (C57BL/6)
Maximum bicarbonate signal was reduced 7-fold in the mouse heart compared to the rat heart (0.023 ± 0.001 a.u. vs 0.165 ± 0.008 a.u. bicarbonate normalized to peak pyruvate signal)
Summary
Alterations in cardiac metabolism accompany many diseases of the heart. The advent of cardiac hyperpolarized magnetic resonance spectroscopy (MRS), via dynamic nuclear polarization (DNP), has enabled a greater understanding of the in vivo metabolic changes that occur as a consequence of myocardial infarction, hypertrophy and diabetes. Transgenic and knockout (KO) mouse lines enable individual metabolic pathways to be probed, yielding valuable insights into the etiology of human heart disease. Metabolomic techniques, including 1H-nuclear magnetic resonance (NMR), gas chromatography– mass spectrometry (MS) and liquid chromatography-MS have enabled detection of millimolar to sub-picomolar changes of metabolite levels/concentrations in disease [6,7]. These techniques all require the collection of tissue at specific time points, failing to allow serial measurements to be made in the same animal during the progression of a disease
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