Validation of the in vivo assessment of pyruvate dehydrogenase activity using hyperpolarised 13C MRS.
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.
Atherton
Helen J
HJ
Department of Physiology, Anatomy and Genetics, University of Oxford.
Schroeder
Marie A
MA
Department of Physiology, Anatomy and Genetics, University of Oxford.
Dodd
Michael S
MS
Department of Physiology, Anatomy and Genetics, University of Oxford.
Heather
Lisa C
LC
Department of Physiology, Anatomy and Genetics, University of Oxford.
Carter
Emma E
EE
Department of Physiology, Anatomy and Genetics, University of Oxford.
Cochlin
Lowri E
LE
Department of Physiology, Anatomy and Genetics, University of Oxford.
Nagel
Simon
S
Nuffield Department of Clinical Medicine, University of Oxford.|Department of Neurology, University of Heidelberg, Germany.
Sibson
Nicola R
NR
CRUK-MRC Gray Institute for Radiation Oncology and Biology, University of Oxford.
Radda
George K
GK
Department of Physiology, Anatomy and Genetics, University of Oxford.
Clarke
Kieran
K
Department of Physiology, Anatomy and Genetics, University of Oxford.
Tyler
Damian J
DJ
Department of Physiology, Anatomy and Genetics, University of Oxford.
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
D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates
Comput Biol Med. 2001 Jul;31(4):269-86
11334636
Arch Biochem Biophys. 1978 Nov;191(1):65-81
216317
FASEB J. 2009 Aug;23(8):2529-38
19329759
Physiol Rev. 2005 Jul;85(3):1093-129
15987803
Biochem J. 1989 Mar 1;258(2):529-33
2705997
Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10158-63
12930897
Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11270-5
16837573
J Clin Invest. 1998 Jan 1;101(1):79-85
9421469
J Mol Cell Cardiol. 1996 Feb;28(2):341-50
8729066
Diabetes. 2003 Jan;52(1):199-204
12502513
Am J Physiol. 1995 Apr;268(4 Pt 1):E752-7
7733276
Eur J Appl Physiol Occup Physiol. 1980 Feb;43(1):83-91
7371630
J Mol Cell Cardiol. 1997 Oct;29(10):2771-8
9344771
J Mol Cell Cardiol. 1997 Jul;29(7):1867-75
9236140
Biochem J. 1998 Jan 1;329 ( Pt 1):197-201
9405294
Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12051-6
18689683
Curr Probl Cardiol. 1994 Feb;19(2):59-113
8174388
Nature. 1975 Oct 30;257(5529):808-9
171583
Biochem J. 1982 Dec 15;208(3):577-81
6131668
Biochem J. 1973 Jun;134(2):651-3
16742828
J Magn Reson. 2010 Jan;202(1):85-92
19884027
Acta Physiol Scand. 1961 Jul-Aug;52:328-42
13876644
Biochemistry. 1992 Sep 22;31(37):8916-23
1390679
Am J Physiol. 1998 Feb;274(2):E377-80
9486171
J Physiol. 2005 Jan 15;562(Pt 2):593-603
15550462
Biochem J. 1983 Jan 15;210(1):193-8
6405740
FEBS Lett. 1993 Dec 28;336(3):501-5
8282119
Biochem Soc Trans. 2001 May;29(Pt 2):272-8
11356166
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19773-7
18056642
Metabolism. 1971 Feb;20(2):149-67
5540184
Curr Top Cell Regul. 1981;18:95-106
7273851
J Biol Chem. 1978 Apr 25;253(8):2716-23
632296
Biochem Soc Trans. 1986 Oct;14(5):799-806
3536635
Circulation. 2002 Jul 30;106(5):606-12
12147544
Magn Reson Med. 2009 May;61(5):1007-14
19253408
Am J Physiol Heart Circ Physiol. 2003 Jul;285(1):H270-6
12663261
J Nucl Med. 1978 Dec;19(12):1311-9
104018