Mechanisms contributing to muscle-wasting in acute uremia: activation of amino acid catabolism.
Acute uremia (ARF) causes metabolic defects in glucose and protein metabolism that contribute to muscle wasting. To examine whether there are also defects in the metabolism of essential amino acids in ARF, we measured the activity of the rate-limiting enzyme for branched-chain amino acid catabolism, branched-chain ketoacid dehydrogenase (BCKAD), in rat muscles. Because chronic acidosis activates muscle BCKAD, we also evaluated the influence of acidosis by studying ARF rats given either NaCl (ARF-NaCl) or NaHCO3 (ARF-HCO3) to prevent acidosis, and sham-operated, control rats given NaHCO3. ARF-NaCl rats became progressively acidemic (serum [HCO3] = 21.3 +/- 0.7 mM within 18 h and 14.7 +/- 0.8 mM after 44 h; mean +/- SEM), but this was corrected with NaHCO3. Plasma valine was low in ARF-NaCl and ARF-HCO3 rats. Plasma isoleucine, but not leucine, was low in ARF-NaCl rats, and isoleucine tended to be lower in ARF-HCO3 rats. Basal BCKAD activity (a measure of active BCKAD in muscle) was increased more than 17-fold (P < 0.01) in ARF-NaCl rat muscles, and this response was partially suppressed by NaHCO3. Maximal BCKAD activity (an estimate of BCKAD content), subunit mRNA levels, and BCKAD protein content were not different in ARF and control rat muscles. Thus, ARF increases branched-chain amino acid catabolism by activating BCKAD by a mechanism that includes acidosis. Moreover, in a muscle-wasting condition such as ARF, there is a coordinated increase in protein and essential amino acid catabolism.
Price
S R
SR
Renal Division, Emory University School of Medicine, Atlanta, Georgia, USA.
Reaich
D
D
Marinovic
A C
AC
England
B K
BK
Bailey
J L
JL
Caban
R
R
Mitch
W E
WE
Maroni
B J
BJ
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000138:Acidosis / Q000517:prevention & control; D000208:Acute Disease; D000284:Administration, Oral; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002254:Carbonates / Q000008:administration & dosage / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D007527:Isoenzymes / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D007532:Isoleucine / Q000097:blood / Q000187:drug effects; D007658:Ketone Oxidoreductases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D009097:Multienzyme Complexes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D046249:Transfer RNA Aminoacylation; D014511:Uremia / Q000378:metabolism*; D014633:Valine / Q000097:blood / Q000187:drug effects; D019282:Wasting Syndrome / Q000378:metabolism*
D000596:Amino Acids; D002254:Carbonates; D007527:Isoenzymes; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D007532:Isoleucine; C005686:sodium carbonate; D007658:Ketone Oxidoreductases; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D014633:Valine