title: Endotoxin-induced growth hormone resistance in skeletal muscle.
abstract: Inflammation-induced skeletal muscle wasting is a serious clinical problem and arises in part because of resistance to GH-stimulated IGF-I expression. Although it is established that in the liver, resistance develops because of impaired signaling through the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) transduction pathway, together with a more distal defect in STAT5 DNA-binding activity, the situation in skeletal muscle is unclear. Accordingly, we set out to characterize the mechanisms behind the skeletal muscle resistance to GH in rats with acute inflammation induced by endotoxin. Endotoxin caused significant declines in GH-stimulated STAT5a/b phosphorylation and IGF-I gene expression, and this occurred despite a lack of change in signaling protein levels or phosphorylation of JAK2. In whole muscle, GH-stimulated phospho-STAT5a/b levels were reduced by half, and in the nucleus, phospho-STAT5b levels were similarly reduced. Furthermore, the binding of phosphorylated STAT5b to DNA was reduced and to a similar extent to the reduction in nuclear phosphorylated STAT5b. Interestingly, GH-induced androgen receptor gene expression was also suppressed. Thus, it appears that skeletal muscle resistance to GH-stimulated IGF-I expression in acute endotoxemia arises from a defect in STAT5b signaling, with a proportionate reduction in STAT5b DNA binding. Finally, it appears that resistance to GH-induced androgen receptor expression also develops and, together with the attenuated GH-induced IGF-I expression, likely plays an important role in the muscle wasting that arises in endotoxin-induced inflammation.
authors.affiliation: Department of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Sumita
authors.initials: S
authors.lastname: Sood
authors.forename: Vidya M R
authors.initials: VM
authors.lastname: Krishnamurthy
authors.forename: Peter
authors.initials: P
authors.lastname: Rotwein
authors.forename: Ralph
authors.initials: R
authors.lastname: Rabkin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D013006:Growth Hormone / Q000494:pharmacology*; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D053614:Janus Kinase 2 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011485:Protein Binding / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D050799:STAT5 Transcription Factor; C494097:Stat5b protein, rat; D013006:Growth Hormone; D004247:DNA; D053614:Janus Kinase 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509250:Ptpn6 protein, rat