We. Mitch et al., Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting, AM J P-CELL, 45(5), 1999, pp. C1132-C1138
The ubiquitin-proteasome proteolytic system is stimulated in conditions cau
sing muscle atrophy. Signals initiating this response in these conditions a
re unknown, although glucocorticoids are required but insufficient to stimu
late muscle proteolysis in starvation, acidosis, and sepsis. To identify si
gnals that activate this system, we studied acutely diabetic rats that had
metabolic acidosis and increased corticosterone production. Protein degrada
tion was increased 52% (P < 0.05), and mRNA levels encoding ubiquitin-prote
asome system components, including the ubiquitin-conjugating enzyme E2(14k)
, were higher (transcription of the ubiquitin and proteasome subunit C3 gen
es in muscle was increased by nuclear run-off assay). In diabetic rats, pre
vention of acidemia by oral NaHCO3 did not eliminate muscle proteolysis. Ad
renalectomy blocked accelerated proteolysis and the rise in pathway mRNAs;
both responses were restored by administration of a physiological dose of g
lucocorticoids to adrenalectomized, diabetic rats. Finally, treating diabet
ic rats with insulin for greater than or equal to 24 h reversed muscle prot
eolysis and returned pathway mRNAs to control levels. Thus acidification is
not necessary for these responses, but glucocorticoids and a low insulin l
evel in tandem activate the ubiquitin-proteasome proteolytic system.