Role of activation of myocardial branched-chain 2-oxo acid dehydrogenase complex in the regulation of leucine decarboxylation during cardiac work in vitro.
The oxidative decarboxylation of L-[1-14C]leucine was measured in the isolated perfused rat heart under both working and non-working conditions. Stimulation of decarboxylation of the labelled substrate was observed in working hearts as cardiac work was increased, and in Langendorff hearts upon increasing the coronary flow rate. The rate of L-[1-14C]leucine decarboxylation was significantly higher (P less than 0.05) in hearts working against moderate afterload pressure when compared to Langendorff hearts perfused at a matching coronary flow rate. The rate of release of 4-methyl-2-oxo[1-14C]pentanoate to the perfusate was high in Langendorff hearts, and was unaffected by changes in coronary flow. In contrast, perfusate levels of 14C-labelled 4-methyl-2-oxopentanoate decreased significantly upon the establishment of the working condition (P less than 0.05). These findings suggested an enhancement in the efficiency of the decarboxylation of the 2-oxo acid in response to cardiac work. The amount of branched-chain 2-oxo acid dehydrogenase complex present in the active form was measured in freeze-clamped hearts. Cardiac work resulted in a rapid activation of the complex (P less than 0.02) within 5 min of work when compared to control Langendorff hearts perfused at matching coronary flow rates. To a lesser extent, increasing the coronary flow rate in Langendorff-perfused hearts also led to activation of the enzyme complex. These studies suggest the following: a) L-leucine oxidation in myocardial tissue can be accelerated by exercise as it is in other tissues; b) this regulatory response can be evoked by the contractile activity of the heart itself, independent of contributions by circulating factors or nervous stimuli; and c) regulation of the activity state of the branched-chain 2-oxo acid dehydrogenase complex is involved in the mechanism by which metabolic flux through this pathway is controlled during cardiac work.
Department of Biochemistry, University of Texas Health Science Center, San Antonio 78284-7760.
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Hildebrandt
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Olson
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000818:Animals; D002208:Caproates / Q000378:metabolism; D003326:Coronary Circulation; D004789:Enzyme Activation; D007651:Keto Acids / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism*; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D002208:Caproates; D007651:Keto Acids; D009097:Multienzyme Complexes; C013082:alpha-ketoisocaproic acid; D007658:Ketone Oxidoreductases; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D007930:Leucine