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1 Department of Cellular and Molecular Physiology, and Surgery, Pennsylvania State College of Medicine, Hershey, PA, USA
* To whom correspondence should be addressed. E-mail: lqh10{at}psu.edu.
Growth hormone (GH) stimulates insulin-like growth factor (IGF)-I synthesis in both liver and muscle. During sepsis, proinflammatory cytokines inhibit GH action in liver but it is unknown whether sepsis also produces GH resistance in muscle. Sepsis was induced by cecal ligation and puncture and 18 h later the effect of GH on STAT phosphorylation and IGF-I mRNA content was assessed in rat gastrocnemius and liver. The relative abundance of phosphorylated (p)STAT5a, STAT5b, STAT3 and STAT1 was increased in liver from control rats after GH. Sepsis alone also increased hepatic pSTAT5a, pSTAT3 and pSTAT1. Sepsis dramatically impaired the ability of GH to stimulate the phosphorylation of STAT5a and 5b as well as to increase IGF-I mRNA in liver. In muscle from control rats, GH increased pSTAT5a and 5b, while content of pSTAT3 and pSTAT1 was not affected. Sepsis increased basal content of pSTAT3 but not pSTAT5a, pSTAT5b or pSTAT1 in muscle. The GH-induced increase of pSTAT5a and 5b in muscle from septic rats was not inhibited suggesting that muscle was not GH resistant. In contrast to these changes in pSTAT5, the ability of GH to increase IGF-I mRNA was completely absent in muscle from septic rats. Because the SOCS (suppressor of cytokine signaling) proteins may function as negative regulators of GH signaling, we examined the content of these proteins. Sepsis produced small (30-50%), albeit statistically significant, increases in SOCS-1, -2, and -3 protein in muscle. In contrast to muscle, the SOCS proteins in the liver did not change under the various experimental conditions suggesting that these proteins are not responsible for the impaired phosphorylation of STAT5 by GH. In conclusion, sepsis produces GH resistance in both muscle and liver with the locus of this impairment in muscle differing from that in liver and being independent of a defect in STAT5 phosphorylation.
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