Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting

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.