In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog.
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.
Holtzman
D
D
Department of Neurology, Children's Hospital, Boston, Massachusetts, USA. holtzman@al.tch.harvard.edu
Meyers
R
R
O'Gorman
E
E
Khait
I
I
Wallimann
T
T
Allred
E
E
Jensen
F
F
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
D006146:Guanidines; D011422:Propionates; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D003401:Creatine; C005775:guanidinopropionic acid