Muscle protein breakdown during sepsis is associated with upregulated expression and activity of the ubiquitin-proteasome proteolytic pathway. Previous studies suggest that ubiquitination of proteins in skeletal muscle is regulated by the ubiquitin ligase E3 alpha together with the 14 kDa ubiquitin-conjugating enzyme E2(14k). The E3 alpha gene was cloned only recently. The influence of sepsis on the gene expression of E3 alpha in skeletal muscle has not been reported. In the present study, induction of sepsis in rats by cecal ligation and puncture resulted in increased mRNA levels for E3 alpha in white, fast-twitch but not in red slow-twitch muscle. Treatment with the glucocorticoid receptor antagonist RU38486 (10 mg/kg) prevented the sepsis-induced increase in E3 alpha and E2(14k) mRNA levels. The present study is the first report of increased E3 alpha expression in skeletal muscle during sepsis. The results lend further support to the concept that glucocorticoid-mediated upregulation of the ubiquitin-proteasome proteolytic pathway is involved in sepsis-induced muscle cachexia. Increased expression of both E3 alpha and E2(14k) suggests that muscle proteins are degraded in the N-end rule pathway during sepsis.