Effect of the glucocorticoid receptor antagonist RU 38486 on muscle protein breakdown in sepsis

The role of glucocorticoids in muscle catabolism during sepsis was tested with the glucocorticoid receptor antagonist RU 38486. Sepsis was induced in male Sprague-Dawley rats (40 to 60 gm) by cecal ligation and puncture (CLP). Other animals underwent sham operation. Two hours before CLP or sham operation, rats received RU 38486 (5 mg/kg) or a corresponding volume of vehicle by gavage. Sixteen hours after CLP or sham operation, protein synthesis rate was determined by measuring incorporation of 14C-phenylalanine into protein in incubated extensor digitorum longus muscles. Total and myofibrillar protein breakdown rates were determined by measuring net release of tyrosine and 3-methylhistidine, respectively. The protein synthesis rate was approximately 30% lower in rats with sepsis than in sham operated rats and was not affected by treatment with RU 38486. The total protein breakdown rate was increased by approximately 70% and myofibrillar protein degradation was increased more than fivefold in muscle from rats with sepsis. Treatment with RU 38486 resulted in a 28% reduction of total and a 44% reduction of myofibrillar protein breakdown in rats with sepsis but did not affect proteolysis in muscle from sham-operated animals. The results support a role of glucocorticoids in accelerated muscle proteolysis during sepsis. It is not clear whether glucocorticoids are the only required mediator or they interact with other substances to induce muscle protein breakdown during sepsis.