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1 Department of Surgery, University of Cincinnati, Cincinnati 45267-0558; and 2 Shriners Hospitals for Children, Cincinnati, Ohio 45229-3095
Sepsis-induced muscle cachexia is
associated with increased expression of several genes in the
ubiquitin-proteasome proteolytic pathway, but little is known about the
activation of transcription factors in skeletal muscle during sepsis.
We tested the hypothesis that sepsis upregulates the expression and
activity of the transcription factors CCAAT/enhancer binding protein
(C/EBP)-
and -
in skeletal muscle. Sepsis was induced in
rats by cecal ligation and puncture, and control rats were sham
operated. C/EBP-
and -
DNA-binding activity was determined by
electrophoretic mobility shift assay and supershift analysis. In
addition, C/EBP-
and -
nuclear protein levels were determined by
Western blot analysis. Sepsis resulted in increased DNA-binding
activity of C/EBP, and supershift analysis suggested that this
reflected activation of the
- and
-isoforms of C/EBP.
Concomitantly, C/EBP-
and -
protein levels were increased in the
nuclear fraction of skeletal muscle. In additional experiments, we
tested the role of glucocorticoids in sepsis-induced activation of
C/EBP-
and -
by treating rats with the glucocorticoid receptor antagonist RU-38486. This treatment inhibited the
sepsis-induced activation of C/EBP-
and -
, suggesting that
glucocorticoids participate in the upregulation of C/EBP in skeletal
muscle during sepsis. The present results suggest that C/EBP-
and
-
are activated in skeletal muscle during sepsis and that this
response is, at least in part, regulated by glucocorticoids.
transcription factors; cachexia; proteolysis; ubiquitin; proteasome; CCAAT/enhancer binding protein; deoxyribonucleic acid
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