title: Inhibition of the electron transport chain and creatine kinase activity by ethylmalonic acid in human skeletal muscle.
abstract: Ethylmalonic aciduria is a common finding in patients affected by short-chain acyl-CoA dehydrogenase (SCAD) deficiency and other diseases characterized by encephalopathy, muscular symptomatology, and lactic acidemia. Considering that the pathophysiological mechanisms of these disorders are practically unknown and that lactic acidosis suggest an impairment of energy production, the objective of the present work was to investigate the in vitro effect of ethylmalonic acid (EMA), at concentrations varying from 0.25 to 5.0 mM, on important parameters of energy metabolism in human skeletal muscle, such as the activities of the respiratory chain complexes and of creatine kinase, which are responsible for most of the ATP produced and transferred inside the cell. We verified that EMA significantly inhibited the activity of complex I-III at concentrations as low as 0.25 mM, complex II-III at 1 mM and higher concentrations, and complex II at the concentration of 5 mM. In contrast, complex IV was not inhibited by the acid. Finally, we observed that the activity of creatine kinase was significantly inhibited by EMA at the concentrations of 1 and 5 mM. These results suggest that EMA compromises energy metabolism in human skeletal muscle. In case the in vitro effects detected in the present study also occur in vivo, it is tempting to speculate that they may contribute, at least in part, to explain the hypotonia/myopathy, as well as the increased concentrations of lactic acid present in the patients affected by illnesses in which EMA accumulates.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Alethea G
authors.initials: AG
authors.lastname: Barschak
authors.forename: Gustavo da C
authors.initials: Gda C
authors.lastname: Ferreira
authors.forename: Karina R
authors.initials: KR
authors.lastname: André
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Schuck
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Viegas
authors.forename: Anelise
authors.initials: A
authors.lastname: Tonin
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Dutra Filho
authors.forename: Angela T S
authors.initials: AT
authors.lastname: Wyse
authors.forename: Clóvis M D
authors.initials: CM
authors.lastname: Wannmacher
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Vargas
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000140:Acidosis, Lactic / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D003402:Creatine Kinase / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000378:metabolism; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008314:Malonates / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D045222:Electron Transport Chain Complex Proteins; D008314:Malonates; C038080:ethylmalonic acid; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D003402:Creatine Kinase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III