The balance between glucocorticoids and insulin regulates muscle proteolysis via the ubiquitin-proteasome pathway

In uremia, accelerated muscle protein degradation results from activation o f the ATP-ubiquitin proteasome proteolytic pathway. Like uremia, other cond itions (e.g., acidosis and diabetes) activate this pathway in rat muscles a nd are associated with excess glucocorticoids (GC) and impaired insulin act ion. To define the stimuli responsible for muscle wasting in IDDM, the role s of glucocorticoids, insulinopenia and acidosis in streptozotocin (STZ)- i nduced diabetes were studied. Proteolysis in isolated epitrochlearis muscle s from acutely (3d) diabetic rats was 52% higher than pair-fed, sham-inject ed rats; this increase was eliminated by an inhibitor of the proteasome or by blocking AIP synthesis. In muscles of STZ-diabetic rats, the levels of u biquitin-conjugated proteins and mRNAs encoding ubiquitin, the ubiquitin-ca rrier protein, E2(14k) and the C3, C5 and C9 proteasome subunits were incre ased. Transcription of ubiquitin and C3 proteasome subunit genes in muscle was also increased by IDDM. Oral NaHCO3 eliminated acidemia but did not pre vent accelerated muscle proteolysis. Corticosterone excretion was higher in IDDM rats and adrenalectomy (ADX) prevented these catabolic responses; phy siologic doses of glucorcoticoids restored the excessive protein catabolism in ADX-STZ rats. Giving IDDM rats replacement insulin also normalized prot ein degradation in muscles. In conclusion, reduced insulin together with ph ysiologic levels of glucocorticoids activate the ubiquitin-proteasome pathw ay by a mechanism that includes enhancing ubiquitin conjugation and proteol ysis by the proteasome. The balance between these stimuli could regulate mu scle proteolysis in uremia. Copyright (C) 2000 S. Karger AG, Basel.