title: In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog.
abstract: 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 transport, was used to study the hypothesis that the creatine-CK-phosphocreatine (PCr) system is important in regulating brain ATP metabolism. The CK-catalyzed reaction rate and reactant concentrations were measured in vivo with 31P nuclear magnetic resonance spectroscopy during energy deficit (hypoxia) or high-energy turnover (seizures) states in urethane-anesthetized mice fed GPA, creatine, or standard chow (controls). Brain phosphagen (i.e., cellular energy reserves) or PCr plus phosphorylated GPA (GPAP) concentrations were equal. The phosphagen-to-NTP ratio was lower than in controls. In vivo CK reaction rate decreased fourfold, whereas ex vivo CK activity that was biochemically measured was doubled. During seizures, CK-catalyzed fluxes increased only in GPA-fed mice. Phosphagen increased in GPA-fed mice, whereas PCr decreased in controls. Survival was higher and brain phosphagen and ATP losses were less for hypoxic GPA-fed mice than for controls. In contrast to mice fed GPA, hypoxic survival and CK reactant concentrations during hypoxia and seizures were the same in creatine-fed mice and controls. Thus GPA, GPAP, or adaptive changes in ATP metabolism stabilize brain ATP and enhance survival during hypoxia in mice.
authors.affiliation: Department of Neurology, Children's Hospital, Boston, Massachusetts, USA. holtzman@al.tch.harvard.edu
authors.forename: D
authors.initials: D
authors.lastname: Holtzman
authors.forename: R
authors.initials: R
authors.lastname: Meyers
authors.forename: E
authors.initials: E
authors.lastname: O'Gorman
authors.forename: I
authors.initials: I
authors.lastname: Khait
authors.forename: T
authors.initials: T
authors.lastname: Wallimann
authors.forename: E
authors.initials: E
authors.lastname: Allred
authors.forename: F
authors.initials: F
authors.lastname: Jensen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003401:Creatine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism; D004032:Diet; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D010725:Phosphocreatine / Q000378:metabolism*; D010766:Phosphorylation; D011422:Propionates / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D012640:Seizures / Q000378:metabolism
chemical_list: D006146:Guanidines; D011422:Propionates; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D003401:Creatine; C005775:guanidinopropionic acid