Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase.
Protein catabolic states (i.e., sepsis and trauma) are thought to be associated with accelerated oxidation of branched-chain amino acids (BCAA). Branched-chain alpha-keto acid dehydrogenase (BCKAD), the rate-limiting enzyme for BCAA oxidation by muscle, is regulated by phosphorylation/dephosphorylation. Skeletal muscle BCKAD was only 2-4% active in control rats. Intravenous injection of Salmonella enteritidis endotoxin (0.25-10 mg/kg) did not change total BCKAD activity, but increased the percent active enzyme in muscle three- to four-fold in 4-6 h. Identical results were observed in adrenalectomized rats pretreated with one dose of alpha-methylprednisolone (2.5 mg/kg i.p.) 30-60 min before saline or endotoxin injection, indicating that endotoxin's effect was not mediated by hypersecretion of adrenal hormones. Cortisone pretreatment of normal rats (100 mg/kg per d) for 2 d prevented endotoxin-induced activation of muscle BCKAD, suggesting that endogenous secretion products mediated BCKAD activation by endotoxin. Human recombinant tumor necrosis factor-alpha and/or IL-1 beta or alpha (50 micrograms/kg) increased muscle BCKAD activation two- to fourfold in normal rats 4-6 h after intravenous injection. We conclude that cytokine-mediated activation of muscle BCKAD may contribute to accelerated BCAA oxidation in septicemia.
Nawabi
M D
MD
Department of Medicine, Medical University of South Carolina, Charleston 29425.
Block
K P
KP
Chakrabarti
M C
MC
Buse
M G
MG
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004731:Endotoxins / Q000494:pharmacology*; D004789:Enzyme Activation; D007375:Interleukin-1 / Q000494:pharmacology*; D007658:Ketone Oxidoreductases / Q000378:metabolism*; D007700:Kinetics; D007930:Leucine / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism*; D009132:Muscles / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D012477:Salmonella enteritidis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000596:Amino Acids; D004731:Endotoxins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007658:Ketone Oxidoreductases; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D007930:Leucine; D003345:Corticosterone