Insulin-like growth factor I reduces ubiquitin and ubiquitin-conjugating enzyme gene expression but does not inhibit muscle proteolysis in septic rats

We examined the effect of insulin-like growth factor I (IGF-I), administere d in vivo, on protein turnover rates and gene expression of the ubiquitin-p roteasome proteolytic pathway in skeletal muscle of septic rats. Sepsis was induced by cecal ligation and puncture. Other rats were sham-operated. Min iosmotic pumps were implanted sc, and groups of rats received IGF-I (7 mg/k g.24 h) or saline. Protein synthesis and breakdown rates were determined in incubated extensor digitorum longus muscles. Messenger RNA levels for ubiq uitin and the ubiquitin-conjugating enzyme E2(14k) were determined by North ern blot analysis. Sepsis resulted in an approximately 30% reduction of mus cle protein synthesis, and this effect of sepsis was blunted in rats treate d with IGF-I. In contrast, IGF-I did not prevent the sepsis-induced increas e in total and myofibrillar muscle protein breakdown. Ubiquitin and E2(14k) messenger RNA levels were increased several fold in muscle from septic rat s, and this effect of sepsis was abolished in IGF-I treated rats. The resul ts suggest that administration of IGF-I may improve sepsis-induced muscle c achexia by stimulating protein synthesis. However, because muscles were res istant to IGF-I, with regard to regulation of protein breakdown, the use of IGF-I to treat muscle cachexia during sepsis remains unclear. An additiona l important implication of the present study is that changes in messenger R NA levels for ubiquitin and the ubiquitin-conjugating enzyme E2(14k) do not always reflect changes in muscle protein breakdown rates.