Transcription factors in skeletal muscle during sepsis

University Of Cincinnati, Cincinnati OH

Investigators

Abstract

DESCRIPTION: (Provided By Applicant) Muscle cachexia, mainly reflecting ubiquitin-proteasome-dependent protein breakdown, is one of the metabolic hallmarks of sepsis. Previous studies suggest that gene expression and activity of the ubiquitin-proteasome pathway are upregulated in septic skeletal muscle. Despite the fact that the transcription of several genes in this proteolytic pathway are activated, there is no information regarding the influence of sepsis on the activity of transcription factors in skeletal muscle. The purpose of this project is to study the influence of sepsis in rats on the expression and activity of the "inflammatory" transcription factors, NF-KB, AP-1 and C/EBP. Because glucocorticoids regulate sepsis-induced muscle proteolysis, I will also investigate the role of glucocorticoids in sepsis-induced changes in transcription factor activity in skeletal muscle. In addition, treatment of cultured L6 myotubes with dexamethasone will be used as a "cachectic model" to investigate the expression and activity of NF-KB, AP-1 and C/EBP. The proposed experiments are important because they will further define the molecular regulation of sepsis-induced muscle proteolysis. The experiments in the cultured myotubes will make it possible to test direct effects of glucocorticoids on gene activation by the transcription factors. Knowledge gained from the proposed experiments will make it possible in the future to define genes in the ubiquitin-proteasome-proteolytic pathway that are rate limiting in sepsis/glucocorticoid-induced proteolysis.