In vivo brain phosphocreatine and atp regulation in mice fed a
creatine analogue.
Holtzman, D., R. Meyers, E. O'gorman, I. Khait, T. Wallimann, E.
Allred, F. Jensen.
Department of Neurology, Children's Hospital and Harvard Medical
School, 300 Longwood Ave., Boston, MA 02115, USA, Institute for Cell
Biology, ETH-Honggerberg, CH-8093 Zurich, Switzerland
APStracts 3:0391C, 1996.
Mitochondrial and cytosolic creatine kinase (CK) isozymes are active
in cells with high and variable ATP metabolic rates. [beta]
-guanidinopropionic acid (GPA), a competitive inhibitor of creatine
(Cr) transport, was used to study the hypothesis that the
Cr/CK/phosphocreatine (PCr) system is important in regulating brain
ATP metabolism. The CK catalyzed reaction rate and reactant
concentrations were measured in vivo using 31P nuclear magnetic
resonance spectroscopy during energy deficit (hypoxia) or high energy
turnover (seizures) states in urethane anesthetized mice fed GPA, Cr,
or standard chow (Controls). Brain phosphagen (i.e., cellular energy
reserves) or PCr plus phosphorylated GPA (GPAP) concentrations were
equal. Phosphagen/nucleoside triphosphate was lower than in Controls.
In vivo CK reaction rate decreased four fold, while ex vivo
biochemically measured CK activity doubled. During seizures CK
catalyzed fluxes increased in GPA fed mice only. Phosphagen increased
in GPA fed mice while PCr decreased in Controls. Survival was higher
and brain phosphagen and ATP losses less in hypoxic GPA fed mice than
Controls. In contrast to mice fed GPA, hypoxic survival and CK
reactant concentrations during hypoxia and seizures were the same in
Cr fed mice and Controls. Thus, GPA, GPAP, or adaptive changes in ATP
metabolism stabilize brain ATP and enhance survival during hypoxia in
mice.
Received 12 August 1996; accepted in final form 21 November 1996.
APS Manuscript Number C457-6.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996