Kinetic modeling of hyperpolarized 13C1-pyruvate metabolism in normal rats and TRAMP mice

UCSF/UCB Joint Graduate Group in Bioengineering, San Francisco, CA 94143-2532, USA.
Journal of Magnetic Resonance (Impact Factor: 2.51). 10/2009; 202(1):85-92. DOI: 10.1016/j.jmr.2009.10.003
Source: PubMed


To investigate metabolic exchange between (13)C(1)-pyruvate, (13)C(1)-lactate, and (13)C(1)-alanine in pre-clinical model systems using kinetic modeling of dynamic hyperpolarized (13)C spectroscopic data and to examine the relationship between fitted parameters and dose-response.
Dynamic (13)C spectroscopy data were acquired in normal rats, wild type mice, and mice with transgenic prostate tumors (TRAMP) either within a single slice or using a one-dimensional echo-planar spectroscopic imaging (1D-EPSI) encoding technique. Rate constants were estimated by fitting a set of exponential equations to the dynamic data. Variations in fitted parameters were used to determine model robustness in 15 mm slices centered on normal rat kidneys. Parameter values were used to investigate differences in metabolism between and within TRAMP and wild type mice.
The kinetic model was shown here to be robust when fitting data from a rat given similar doses. In normal rats, Michaelis-Menten kinetics were able to describe the dose-response of the fitted exchange rate constants with a 13.65% and 16.75% scaled fitting error (SFE) for k(pyr-->lac) and k(pyr-->ala), respectively. In TRAMP mice, k(pyr-->lac) increased an average of 94% after up to 23 days of disease progression, whether the mice were untreated or treated with casodex. Parameters estimated from dynamic (13)C 1D-EPSI data were able to differentiate anatomical structures within both wild type and TRAMP mice.
The metabolic parameters estimated using this approach may be useful for in vivo monitoring of tumor progression and treatment efficacy, as well as to distinguish between various tissues based on metabolic activity.

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Available from: Ralph Hurd
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    • "The mathematical modeling of an experiment involving hyperpolarized metabolites requires account to be taken of more parameters than those in classical (bio)chemical kinetics. Some of these refinements are well described in the literature (for example,18,19,21) while others are not. In the following sections we explain the different kinetics aspects that arise as a result of the excited (hyperpolarized) state. "
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    ABSTRACT: Rapid-dissolution dynamic nuclear polarization (DNP) has made significant impact in the characterization and understanding of metabolism that occurs on the sub-minute timescale in several diseases. While significant efforts have been made in developing applications, and in designing rapid-imaging radiofrequency (RF) and magnetic field gradient pulse sequences, very few groups have worked on implementing realistic mathematical/kinetic/relaxation models to fit the emergent data. The critical aspects to consider when modeling DNP experiments depend on both nuclear magnetic resonance (NMR) and (bio)chemical kinetics. The former constraints are due to the relaxation of the NMR signal and the application of ‘read’ RF pulses, while the kinetic constraints include the total amount of each molecular species present. We describe the model-design strategy we have used to fit and interpret our DNP results. To our knowledge, this is the first report on a systematic analysis of DNP data.
    Full-text · Article · Feb 2013 · Magnetic Resonance Insights
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    • "The peak areas of [1-13C]pyruvate, [1-13C]lactate, [1-13C]alanine and 13C]bicarbonate at each time point were quantified and used as input data for a kinetic model. The kinetic model developed for the analysis of hyperpolarized [1-13C]pyruvate data is based on a model developed by [19,37]. "
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    ABSTRACT: Background 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. 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 Results In 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. Conclusions We 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.
    Full-text · Article · Feb 2013 · Journal of Cardiovascular Magnetic Resonance
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    • "Color versions of one or more of the figures in this paper are available online at Digital Object Identifier 10.1109/TBME.2011.2161988 a response to treatment [4], [5]. These rates, however, reflect not only intracellular chemical exchange but also membrane transport and pyruvate delivery outside the cell and within the vasculature because of the lack of any contrast between these compartments. "

    Full-text · Article · Jan 2012
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