title: Marked reduction of Na(+), K(+)-ATPase and creatine kinase activities induced by acute lysine administration in glutaryl-CoA dehydrogenase deficient mice.
abstract: Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase activity leading to accumulation of predominantly glutaric (GA) and 3-hydroxyglutaric (3HGA) acids in the brain and other tissues. Affected patients usually present with hypotonia and brain damage and acute encephalopathic episodes whose pathophysiology is not yet fully established. In this study we investigated important parameters of cellular bioenergetics in brain, heart and skeletal muscle from 15-day-old glutaryl-CoA dehydrogenase deficient mice (Gcdh(-/-)) submitted to a single intra-peritoneal injection of saline (Sal) or lysine (Lys - 8 μmol/g) as compared to wild type (WT) mice. We evaluated the activities of the respiratory chain complexes II, II-III and IV, α-ketoglutarate dehydrogenase (α-KGDH), creatine kinase (CK) and synaptic Na(+), K(+)-ATPase. No differences of all evaluated parameters were detected in the Gcdh(-/-) relatively to the WT mice injected at baseline (Sal). Furthermore, mild increases of the activities of some respiratory chain complexes (II-III and IV) were observed in heart and skeletal muscle of Gcdh(-/-) and WT mice after Lys administration. However, the most marked effects provoked by Lys administration were marked decreases of the activities of Na(+), K(+)-ATPase in brain and CK in brain and skeletal muscle of Gcdh(-/-) mice. In contrast, brain α-KGDH activity was not altered in WT and Gcdh(-/-) injected with Sal or Lys. Our results demonstrate that reduction of Na(+), K(+)-ATPase and CK activities may play an important role in the pathogenesis of the neurodegenerative changes in GA I.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
authors.forename: Cristiane
authors.initials: C
authors.lastname: Cecatto
authors.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.forename: Ângela
authors.initials: Â
authors.lastname: Zanatta
authors.forename: Carolina Gonçalves
authors.initials: CG
authors.lastname: Fernandes
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.forename: Luisa Macedo
authors.initials: LM
authors.lastname: Braga
authors.forename: César Augusto João
authors.initials: CA
authors.lastname: Ribeiro
authors.forename: Diogo Onofre Gomes
authors.initials: DO
authors.lastname: de Souza
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.forename: David M
authors.initials: DM
authors.lastname: Koeller
authors.forename: Stephen
authors.initials: S
authors.lastname: Goodman
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001928:Brain Diseases, Metabolic / Q000188:drug therapy / Q000378:metabolism*; D003402:Creatine Kinase / Q000378:metabolism*; D004195:Disease Models, Animal; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008239:Lysine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
chemical_list: D007655:Ketoglutarate Dehydrogenase Complex; D050770:Glutaryl-CoA Dehydrogenase; D003402:Creatine Kinase; D000254:Sodium-Potassium-Exchanging ATPase; D008239:Lysine