title: Validation of the in vivo assessment of pyruvate dehydrogenase activity using hyperpolarised 13C MRS.
abstract: Many diseases of the heart are characterised by changes in substrate utilisation, which is regulated in part by the activity of the enzyme pyruvate dehydrogenase (PDH). Consequently, there is much interest in the in vivo evaluation of PDH activity in a range of physiological and pathological states to obtain information on the metabolic mechanisms of cardiac diseases. Hyperpolarised [1-(13)C]pyruvate, detected using MRS, is a novel technique for the noninvasive evaluation of PDH flux. PDH flux has been assumed to directly reflect in vivo PDH activity, although to date this assumption remains unproven. Control animals and animals undergoing interventions known to modulate PDH activity, namely high fat feeding and dichloroacetate infusion, were used to investigate the relationship between in vivo hyperpolarised MRS measurements of PDH flux and ex vivo measurements of PDH enzyme activity (PDH(a)). Further, the plasma concentrations of pyruvate and other important metabolites were evaluated following pyruvate infusion to assess the metabolic consequences of pyruvate infusion during hyperpolarised MRS experiments. Hyperpolarised MRS measurements of PDH flux correlated significantly with ex vivo measurements of PDH(a), confirming that PDH activity influences directly the in vivo flux of hyperpolarised pyruvate through cardiac PDH. The maximum plasma concentration of pyruvate reached during hyperpolarised MRS experiments was approximately 250 µM, equivalent to physiological pyruvate concentrations reached during exercise or with dietary interventions. The concentrations of other metabolites, including lactate, glucose and β-hydroxybutyrate, did not vary during the 60 s following pyruvate infusion. Hence, during the 60-s data acquisition period, metabolism was minimally affected by pyruvate infusion.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Atherton
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Schroeder
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dodd
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Heather
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Carter
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford.
authors.forename: Lowri E
authors.initials: LE
authors.lastname: Cochlin
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford.|Department of Neurology, University of Heidelberg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Nagel
authors.affiliation: CRUK-MRC Gray Institute for Radiation Oncology and Biology, University of Oxford.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford.
authors.forename: George K
authors.initials: GK
authors.lastname: Radda
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford.
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Tyler
mesh_terms: D000818:Animals; D007700:Kinetics; D008297:Male; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D011773:Pyruvates / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D013053:Spectrophotometry
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates
references.citation: Comput Biol Med. 2001 Jul;31(4):269-86
references.pmid: 11334636
references.citation: Arch Biochem Biophys. 1978 Nov;191(1):65-81
references.pmid: 216317
references.citation: FASEB J. 2009 Aug;23(8):2529-38
references.pmid: 19329759
references.citation: Physiol Rev. 2005 Jul;85(3):1093-129
references.pmid: 15987803
references.citation: Biochem J. 1989 Mar 1;258(2):529-33
references.pmid: 2705997
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10158-63
references.pmid: 12930897
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11270-5
references.pmid: 16837573
references.citation: J Clin Invest. 1998 Jan 1;101(1):79-85
references.pmid: 9421469
references.citation: J Mol Cell Cardiol. 1996 Feb;28(2):341-50
references.pmid: 8729066
references.citation: Diabetes. 2003 Jan;52(1):199-204
references.pmid: 12502513
references.citation: Am J Physiol. 1995 Apr;268(4 Pt 1):E752-7
references.pmid: 7733276
references.citation: Eur J Appl Physiol Occup Physiol. 1980 Feb;43(1):83-91
references.pmid: 7371630
references.citation: J Mol Cell Cardiol. 1997 Oct;29(10):2771-8
references.pmid: 9344771
references.citation: J Mol Cell Cardiol. 1997 Jul;29(7):1867-75
references.pmid: 9236140
references.citation: Biochem J. 1998 Jan 1;329 ( Pt 1):197-201
references.pmid: 9405294
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12051-6
references.pmid: 18689683
references.citation: Curr Probl Cardiol. 1994 Feb;19(2):59-113
references.pmid: 8174388
references.citation: Nature. 1975 Oct 30;257(5529):808-9
references.pmid: 171583
references.citation: Biochem J. 1982 Dec 15;208(3):577-81
references.pmid: 6131668
references.citation: Biochem J. 1973 Jun;134(2):651-3
references.pmid: 16742828
references.citation: J Magn Reson. 2010 Jan;202(1):85-92
references.pmid: 19884027
references.citation: Acta Physiol Scand. 1961 Jul-Aug;52:328-42
references.pmid: 13876644
references.citation: Biochemistry. 1992 Sep 22;31(37):8916-23
references.pmid: 1390679
references.citation: Am J Physiol. 1998 Feb;274(2):E377-80
references.pmid: 9486171
references.citation: J Physiol. 2005 Jan 15;562(Pt 2):593-603
references.pmid: 15550462
references.citation: Biochem J. 1983 Jan 15;210(1):193-8
references.pmid: 6405740
references.citation: FEBS Lett. 1993 Dec 28;336(3):501-5
references.pmid: 8282119
references.citation: Biochem Soc Trans. 2001 May;29(Pt 2):272-8
references.pmid: 11356166
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19773-7
references.pmid: 18056642
references.citation: Metabolism. 1971 Feb;20(2):149-67
references.pmid: 5540184
references.citation: Curr Top Cell Regul. 1981;18:95-106
references.pmid: 7273851
references.citation: J Biol Chem. 1978 Apr 25;253(8):2716-23
references.pmid: 632296
references.citation: Biochem Soc Trans. 1986 Oct;14(5):799-806
references.pmid: 3536635
references.citation: Circulation. 2002 Jul 30;106(5):606-12
references.pmid: 12147544
references.citation: Magn Reson Med. 2009 May;61(5):1007-14
references.pmid: 19253408
references.citation: Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H270-6
references.pmid: 12663261
references.citation: J Nucl Med. 1978 Dec;19(12):1311-9
references.pmid: 104018