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

TLDR

The ubiquitin‑proteasome system is activated in muscle atrophy, yet the initiating signals are unknown, although glucocorticoids are required but not sufficient. The study aimed to identify the signals that activate the ubiquitin‑proteasome system by examining acutely diabetic rats with metabolic acidosis and elevated corticosterone. The authors examined acutely diabetic rats with metabolic acidosis and heightened corticosterone levels to probe the activating signals. Protein degradation rose 52 % and ubiquitin‑proteasome mRNAs were upregulated in diabetic rats, but acidemia prevention did not stop proteolysis; adrenalectomy halted the response, which was restored by glucocorticoids, and insulin treatment reversed proteolysis, showing that glucocorticoids together with low insulin, not acidification, drive the ubiquitin‑proteasome system.

Abstract

The ubiquitin-proteasome proteolytic system is stimulated in conditions causing muscle atrophy. Signals initiating this response in these conditions are unknown, although glucocorticoids are required but insufficient to stimulate muscle proteolysis in starvation, acidosis, and sepsis. To identify signals that activate this system, we studied acutely diabetic rats that had metabolic acidosis and increased corticosterone production. Protein degradation was increased 52% ( P < 0.05), and mRNA levels encoding ubiquitin-proteasome system components, including the ubiquitin-conjugating enzyme E2 14k , were higher (transcription of the ubiquitin and proteasome subunit C3 genes in muscle was increased by nuclear run-off assay). In diabetic rats, prevention of acidemia by oral NaHCO 3 did not eliminate muscle proteolysis. Adrenalectomy blocked accelerated proteolysis and the rise in pathway mRNAs; both responses were restored by administration of a physiological dose of glucocorticoids to adrenalectomized, diabetic rats. Finally, treating diabetic rats with insulin for ≥24 h reversed muscle proteolysis and returned pathway mRNAs to control levels. Thus acidification is not necessary for these responses, but glucocorticoids and a low insulin level in tandem activate the ubiquitin-proteasome proteolytic system.