ENERGY-UBIQUITIN-DEPENDENT MUSCLE PROTEOLYSIS DURING SEPSIS IN RATS IS REGULATED BY GLUCOCORTICOIDS

Recent studies suggest that sepsis-induced increase in muscle proteoly sis mainly reflects energy-ubiquitin-dependent protein breakdown. We t ested the hypothesis that glucocorticoids activate the energy-ubiquiti n-dependent proteolytic pathway in skeletal muscle during sepsis. Rats underwent induction of sepsis by cecal ligation and puncture or were sham-operated and muscle protein breakdown rates were measured 16 h la ter. The glucocorticoid receptor antagonist RU 38486 or vehicle was ad ministered to groups of septic and sham-operated rats. In other experi ments, dexamethasone (2.5 or 10 mg/kg) was injected subcutaneously in normal rats. Total and myofibrillar proteolysis was determined in incu bated extensor digitorum longus muscles as release of tyrosine and 3-m ethylhistidine, respectively. Energy-dependent proteolysis was determi ned in incubated muscles depleted of energy with 2-deoxyglucose and 2, 4-dinitrophenol. Levels of muscle ubiquitin mRNA and free and conjugat ed ubiquitin were determined by Northern and Western blot, respectivel y. RU 38486 inhibited the sepsis-induced increase in total and myofibr illar energy-dependent protein breakdown rates and blunted the increas e in ubiquitin mRNA levels and free ubiquitin. Some, but not all, seps is-induced changes in ubiquitin protein conjugates were inhibited by R U 38486. Injection of dexamethasone in normal rats increased energy-de pendent proteolysis and ubiquitin mRNA levels. The results suggest tha t glucocorticoids regulate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis.