Cerebral creatine kinase deficiency influences metabolite levels and morphology in the mouse brain: a quantitative in vivo 1H and 31P magnetic resonance study.
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.
in 't Zandt
H J A
HJ
Department of Radiology, Nijmegen Centre for Molecular Life Science, University Medical Centre Nijmegen, University of Nijmegen, Nijmegen, The Netherlands.
Renema
W K J
WK
Streijger
F
F
Jost
C
C
Klomp
D W J
DW
Oerlemans
F
F
Van der Zee
C E E M
CE
Wieringa
B
B
Heerschap
A
A
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry / Q000502:physiology*; D003401:Creatine / Q000378:metabolism; D003402:Creatine Kinase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D052276:Creatine Kinase, BB Form; D052281:Creatine Kinase, Mitochondrial Form; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D010759:Phosphorus Isotopes / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
D007527:Isoenzymes; D010759:Phosphorus Isotopes; D014316:Tritium; D003402:Creatine Kinase; D052276:Creatine Kinase, BB Form; D052281:Creatine Kinase, Mitochondrial Form; D003401:Creatine