Effect of In Vivo Administration of Ethylmalonic Acid on Energy Metabolism in Rat Tissues

Abstract

High concentrations of ethylmalonic acid (EMA) occur in tissues and biological fluids of patients affected by deficiency of short-chain acyl-CoA dehydrogenase activity, as well as in other illnesses characterized by neurological and muscular symptoms. Considering that the pathophysiological mechanisms responsible for the clinical manifestations of these diseases are virtually unknown, in the present work we developed a chemical in vivo model of ethylmalonic acidemia in young Wistar rats for neurochemical and behavioral studies through subcutaneous administration of EMA to young rats. The doses of EMA administered subcutaneously varied according to the age of the animals, being injected 3, 4, and 6 μmol g⁻¹ of body weight in rats of 7, 14, and 21 days, respectively. The concentrations of the acid were measured in blood and brain at regular intervals after a single injection (30–120 min) and reached the highest concentrations (3.0 mM and 0.5 μmol g⁻¹, ∼0.5 mM), respectively, after 30 and 60 min of EMA injection. Next, we investigated the effects of acute EMA administration on the activities of complexes I–III, II, II–III, and IV of the respiratory chain in cerebral cortex and skeletal muscle, as well as on the activity of creatine kinase in cerebral cortex, striatum, skeletal muscle, and cardiac muscle of rats of 14 days of life. Control rats were treated with saline in the same volumes. We verified EMA administration did not change these enzymatic activities in all tissues studied. Although transient high concentrations of EMA did not alter important parameters of energy metabolism, it cannot be ruled out that chronic administration of this organic acid would disrupt energy metabolism.