In uremia, accelerated muscle protein degradation results from activation of the ATP-ubiquitin proteasome proteolytic pathway. Like uremia, other conditions (e.g., acidosis and diabetes) activate this pathway in rat muscles and are associated with excess glucocorticoids (GC) and impaired insulin action. To define the stimuli responsible for muscle wasting in IDDM, the roles of glucocorticoids, insulinopenia and acidosis in streptozotocin (STZ) – induced diabetes were studied. Proteolysis in isolated epitrochlearis muscles from acutely (3d) diabetic rats was 52% higher than pair-fed, sham-injected rats; this increase was eliminated by an inhibitor of the proteasome or by blocking ATP synthesis. In muscles of STZ-diabetic rats, the levels of ubiquitin-conjugated proteins and mRNAs encoding ubiquitin, the ubiquitin-carrier protein, E214k and the C3, C5 and C9 proteasome subunits were increased. Transcription of ubiquitin and C3 proteasome subunit genes in muscle was also increased by IDDM. Oral NaHCO3 eliminated acidemia but did not prevent accelerated muscle proteolysis. Corticosterone excretion was higher in IDDM rats and adrenalectomy (ADX) prevented these catabolic responses; physiologic doses of glucorcoticoids restored the excessive protein catabolism in ADX-STZ rats. Giving IDDM rats replacement insulin also normalized protein degradation in muscles. In conclusion, reduced insulin together with physiologic levels of glucocorticoids activate the ubiquitin-proteasome pathway by a mechanism that includes enhancing ubiquitin conjugation and proteolysis by the proteasome. The balance between these stimuli could regulate muscle proteolysis in uremia.

Keywords:
Ubiquitin, Protein degradation, Glucocorticoids, Diabetes, Muscle proteolysis
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2000
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