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), 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.