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Kinetics of creatine uptake in the perfused mouse liver: a 31P-n.m.r. study of transgenic mice expressing creatine kinase (CKBB) in the liver.

ABSTRACT: Transport of creatine in the mouse liver has been investigated in vivo and in the perfused organ. Experiments were carried out with transgenic mice expressing creatine kinase in the liver (brain isoenzyme CKBB; EC 7.2.3.2.) [Koretsky, Brosnan, Chen, Chen and Van Dyke (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 3112-3116] and in the corresponding control mice. The animals were fed a regular chow with or without the addition of 10% creatine (w/w) for 5 days. The kinetics of creatine uptake was measured in the perfused liver by 31P-n.m.r. spectroscopy and biochemical analysis following infusion of creatine at concentrations ranging over 0-15 mM and at an extracellular pH of either 7.40 or 6.40. The results suggest that creatine is actively transported by a pH-dependent mechanism obeying a saturable Michaelis-Menten type of kinetics (Km = 0.80 +/- 0.18 and 5.12 +/- 2.40 mM; Vmax. = 0.57 +/- 0.04 and 1.72 +/- 0.32 mumol.g of liver-1.min-1 at pH 7.40 and 6.40 respectively). Creatine export was evaluated in the perfused liver preloaded with creatine and the results show that less than 2.5 and 5% of the total creatine pool is exported to the perfusate during 80 min of perfusion at pH 7.40 and 6.40 respectively. Taken together, these results seem to explain the observation that creatine accumulates in the mouse liver only when blood creatine is raised by creatine feeding.

SUBMITTER: Masson S

PROVIDER: S-EPMC1137360 | biostudies-other | 1994 Oct

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:The heart's energy demand per gram of tissue is the body's highest and creatine kinase (CK) metabolism, its primary energy reserve, is compromised in common heart diseases. Here, neural-network analysis is used to test whether noninvasive phosphorus (31P) cardiovascular magnetic resonance spectroscopy (CMRS) measurements of cardiac adenosine triphosphate (ATP) energy, phosphocreatine (PCr), the first-order CK reaction rate kf, and the rate of ATP synthesis through CK (CK flux), can predict specific human heart disease and clinical severity. METHODS:The data comprised the extant 178 complete sets of PCr and ATP concentrations, kf, and CK flux data from human CMRS studies performed on clinical 1.5 and 3 Tesla scanners. Healthy subjects and patients with nonischemic cardiomyopathy, dilated (DCM) or hypertrophic disease, New York Heart Association (NYHA) class I-IV heart failure (HF), or with anterior myocardial infarction are included. Three-layer neural-networks were created to classify disease and to differentiate DCM, hypertrophy and clinical NYHA class in HF patients using leave-one-out training. Network performance was assessed using 'confusion matrices' and 'area-under-the-curve' (AUC) analyses of 'receiver operating curves'. Possible methodological bias and network imbalance were tested by segregating 1.5 and 3 Tesla data, and by data augmentation by random interpolation of nearest neighbors, respectively. RESULTS:The network differentiated healthy, HF and non-HF cardiac disease with an overall accuracy of 84% and AUC?>?90% for each category using the four CK metabolic parameters, alone. HF patients with DCM, hypertrophy, and different NYHA severity were differentiated with ~?80% overall accuracy independent of CMRS methodology. CONCLUSIONS:While sample-size was limited in some sub-classes, a neural network classifier applied to noninvasive cardiac 31P CMRS data, could serve as a metabolic biomarker for common disease types and HF severity with clinically-relevant accuracy. Moreover, the network's ability to individually classify disease and HF severity using CK metabolism alone, implies an intimate relationship between CK metabolism and disease, with subtle underlying phenotypic differences that enable their differentiation. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00181259.

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Kinetics of creatine uptake in the perfused mouse liver: a 31P-n.m.r. study of transgenic mice expressing creatine kinase (CKBB) in the liver.

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