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Cerebral creatine kinase deficiency influences metabolite levels and morphology in the mouse brain : a quantitative in vivo 1H and 31P magnetic resonance study

in 't Zandt, H J A LU ; Renema, W K J; Streijger, Femke; Jost, Carolina R; Klomp, D W J; Oerlemans, F; Van der Zee, C E E M; Wieringa, B and Heerschap, Arend (2004) In Journal of Neurochemistry 90(6). p.30-1321
Abstract

Creatine kinase (CK)-catalysed ATP-phosphocreatine (PCr) exchange is considered to play a key role in energy homeostasis of the brain. This study assessed the metabolic and anatomical consequences of partial or complete depletion of this system in transgenic mice without cytosolic B-CK (B-CK-/-), mitochondrial ubiquitous CK (UbCKmit-/-), or both isoenzymes (CK -/-), using non-invasive quantitative magnetic resonance (MR) imaging and spectroscopy. MR imaging revealed an increase in ventricle size in a subset of B-CK-/- mice, but not in animals with UbCKmit or compound CK mutations. Mice lacking single CK isoenzymes had normal levels of high-energy metabolites and tissue pH. In the brains of CK double knockouts pH and ATP and Pi levels... (More)

Creatine kinase (CK)-catalysed ATP-phosphocreatine (PCr) exchange is considered to play a key role in energy homeostasis of the brain. This study assessed the metabolic and anatomical consequences of partial or complete depletion of this system in transgenic mice without cytosolic B-CK (B-CK-/-), mitochondrial ubiquitous CK (UbCKmit-/-), or both isoenzymes (CK -/-), using non-invasive quantitative magnetic resonance (MR) imaging and spectroscopy. MR imaging revealed an increase in ventricle size in a subset of B-CK-/- mice, but not in animals with UbCKmit or compound CK mutations. Mice lacking single CK isoenzymes had normal levels of high-energy metabolites and tissue pH. In the brains of CK double knockouts pH and ATP and Pi levels were also normal, even though PCr had become completely undetectable. Moreover, a 20-30% decrease was observed in the level of total creatine and a similar increase in the level of neuronal N-acetyl-aspartate compounds. Although CKs themselves are not evenly distributed throughout the CNS, these alterations were uniform and concordant across different brain regions. Changes in myo-inositol and glutamate peaks did appear to be mutation type and brain area specific. Our results challenge current models for the biological significance of the PCr-CK energy system and suggest a multifaceted role for creatine in the brain.

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publishing date
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Contribution to journal
publication status
published
keywords
Animals, Brain, Brain Chemistry, Creatine, Creatine Kinase, Creatine Kinase, BB Form, Creatine Kinase, Mitochondrial Form, Isoenzymes, Magnetic Resonance Imaging, Mice, Mice, Inbred C57BL, Mice, Knockout, Nuclear Magnetic Resonance, Biomolecular, Phosphorus Isotopes, Tritium, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
in
Journal of Neurochemistry
volume
90
issue
6
pages
10 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:4544345015
ISSN
0022-3042
DOI
10.1111/j.1471-4159.2004.02599.x
language
English
LU publication?
no
id
6fcc44c2-cdf0-4168-b3cb-f388afb0d0b3
date added to LUP
2017-03-06 17:17:38
date last changed
2017-08-20 05:09:03
@article{6fcc44c2-cdf0-4168-b3cb-f388afb0d0b3,
  abstract     = {<p>Creatine kinase (CK)-catalysed ATP-phosphocreatine (PCr) exchange is considered to play a key role in energy homeostasis of the brain. This study assessed the metabolic and anatomical consequences of partial or complete depletion of this system in transgenic mice without cytosolic B-CK (B-CK-/-), mitochondrial ubiquitous CK (UbCKmit-/-), or both isoenzymes (CK -/-), using non-invasive quantitative magnetic resonance (MR) imaging and spectroscopy. MR imaging revealed an increase in ventricle size in a subset of B-CK-/- mice, but not in animals with UbCKmit or compound CK mutations. Mice lacking single CK isoenzymes had normal levels of high-energy metabolites and tissue pH. In the brains of CK double knockouts pH and ATP and Pi levels were also normal, even though PCr had become completely undetectable. Moreover, a 20-30% decrease was observed in the level of total creatine and a similar increase in the level of neuronal N-acetyl-aspartate compounds. Although CKs themselves are not evenly distributed throughout the CNS, these alterations were uniform and concordant across different brain regions. Changes in myo-inositol and glutamate peaks did appear to be mutation type and brain area specific. Our results challenge current models for the biological significance of the PCr-CK energy system and suggest a multifaceted role for creatine in the brain.</p>},
  author       = {in 't Zandt, H J A and Renema, W K J and Streijger, Femke and Jost, Carolina R and Klomp, D W J and Oerlemans, F and Van der Zee, C E E M and Wieringa, B and Heerschap, Arend},
  issn         = {0022-3042},
  keyword      = {Animals,Brain,Brain Chemistry,Creatine,Creatine Kinase,Creatine Kinase, BB Form,Creatine Kinase, Mitochondrial Form,Isoenzymes,Magnetic Resonance Imaging,Mice,Mice, Inbred C57BL,Mice, Knockout,Nuclear Magnetic Resonance, Biomolecular,Phosphorus Isotopes,Tritium,Comparative Study,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {6},
  pages        = {30--1321},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Neurochemistry},
  title        = {Cerebral creatine kinase deficiency influences metabolite levels and morphology in the mouse brain : a quantitative in vivo 1H and 31P magnetic resonance study},
  url          = {http://dx.doi.org/10.1111/j.1471-4159.2004.02599.x},
  volume       = {90},
  year         = {2004},
}