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Insulin-Like Growth Factor I Reduces Ubiquitin and Ubiquitin-Conjugating Enzyme Gene Expression but Does Not Inhibit Muscle Proteolysis in Septic Rats¹

Department of Surgery, University of Cincinnati, and Shriners Hospital for Children, Cincinnati, Ohio 45267-0558

Address all correspondence and requests for reprints to: Per-Olof Hasselgren, M.D., Department of Surgery, University of Cincinnati, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0558. E-mail: hasselp{at}uc.edu

We examined the effect of insulin-like growth factor I (IGF-I), administered in vivo, on protein turnover rates and gene expression of the ubiquitin-proteasome proteolytic pathway in skeletal muscle of septic rats. Sepsis was induced by cecal ligation and puncture. Other rats were sham-operated. Miniosmotic pumps were implanted sc, and groups of rats received IGF-I (7 mg/kg·24 h) or saline. Protein synthesis and breakdown rates were determined in incubated extensor digitorum longus muscles. Messenger RNA levels for ubiquitin and the ubiquitin-conjugating enzyme E2_14k were determined by Northern blot analysis. Sepsis resulted in an approximately 30% reduction of muscle protein synthesis, and this effect of sepsis was blunted in rats treated with IGF-I. In contrast, IGF-I did not prevent the sepsis-induced increase in total and myofibrillar muscle protein breakdown. Ubiquitin and E2_14k messenger RNA levels were increased several fold in muscle from septic rats, and this effect of sepsis was abolished in IGF-I treated rats. The results suggest that administration of IGF-I may improve sepsis-induced muscle cachexia by stimulating protein synthesis. However, because muscles were resistant to IGF-I, with regard to regulation of protein breakdown, the use of IGF-I to treat muscle cachexia during sepsis remains unclear. An additional important implication of the present study is that changes in messenger RNA levels for ubiquitin and the ubiquitin-conjugating enzyme E2_14k do not always reflect changes in muscle protein breakdown rates.

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