Signals regulating accelerated muscle protein catabolism in uremia.
In chronic renal failure (CRF), the ATP-dependent, ubiquitin-proteasome proteolytic pathway is activated with concurrent increases in the transcription of genes encoding proteins of this pathway in muscle. We have shown that the stimuli for these responses include acidosis and glucocorticoids, but other endocrine abnormalities in CRF (e.g., insulin resistance) could contribute to these responses. In fact, a major effect of insulin in muscle is to suppress protein degradation. To examine whether insulin influences the ubiquitin-proteasome pathway, we measured protein degradation in incubated epitrochlearis muscles of diabetic and pair-fed control rats. Muscle proteolysis was increased in pathways that do not involve lysosomes or Ca(2+)-dependent proteases; but MG132, a protease inhibitor that blocks ATP synthesis, eliminated the accelerated rate of protein degradation in diabetic rat muscles. Diabetes mellitus also increased levels of mRNAs encoding ubiquitin (334%), E2 ubiquitin-conjugating enzyme (247%), and the C3 (320%), C5 (349%), and C9 (216%) proteasome subunits in muscle. Finally, transcription of the ubiquitin gene in diabetic rat muscles was increased. Diabetic rats were acidotic, but eliminating acidemia by giving NaHCO3 did not block the increase in muscle proteolysis. Giving diabetic rats insulin prevented the excessive muscle proteolysis, suggesting that insulin acts as a suppressor of the ubiquitin-proteasome pathway. Thus, the insulin resistance of uremia could contribute to muscle protein wasting in CRF.
Bailey
J L
JL
Renal Division, Emory University School of Medicine, Atlanta, Ga. 30322, USA.
Price
S R
SR
England
B K
BK
Jurkovitz
C
C
Wang
X
X
Ding
X
X
Mitch
W E
WE
D000818:Animals; D015152:Blotting, Northern; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D014511:Uremia / Q000378:metabolism*
D009124:Muscle Proteins