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Inhibition of the Electron Transport Chain and Creatine Kinase Activity by Ethylmalonic Acid in Human Skeletal Muscle

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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.

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Acknowledgment

This work was partly supported by grants from CNPq, PRONEX II, and FAPERGS.

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Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Alethea G. Barschak, Gustavo da C. Ferreira, Karina R. André, Patrícia F. Schuck, Carolina M. Viegas, Anelise Tonin, Carlos S. Dutra Filho, Angela T. S. Wyse, Clóvis M. D. Wannmacher, Carmen R. Vargas & Moacir Wajner

  2. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Carmen R. Vargas & Moacir Wajner

  3. Universidade Luterana do Brasil, Canoas, RS, Brazil

    Moacir Wajner

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  1. Alethea G. Barschak
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  2. Gustavo da C. Ferreira
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  3. Karina R. André
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  4. Patrícia F. Schuck
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  7. Carlos S. Dutra Filho
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  8. Angela T. S. Wyse
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Correspondence to Moacir Wajner.

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Barschak, A.G., Ferreira, G.d.C., André, K.R. et al. Inhibition of the Electron Transport Chain and Creatine Kinase Activity by Ethylmalonic Acid in Human Skeletal Muscle. Metab Brain Dis 21, 11–19 (2006). https://doi.org/10.1007/s11011-006-9000-y

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  • DOI: https://doi.org/10.1007/s11011-006-9000-y

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