Muscle wasting during sepsis and after injury is at least in part mediated by glucocorticoids and mainly reflects ubiquitin-proteasome-dependent protein breakdown. Recent studies suggest that the gene expression of the newly discovered ubiquitin-ligase atrogin-1 is upregulated in atrophying muscle by glucocorticoids. Other studies suggest that the expression and activity of the transcription factors C/EBP Beta and delta are increased but it is not known if C/EBP-Beta and delta regulate the atrogin-I gene in muscle wasting. The role of the nuclear cofactor p300 for gene regulation in atrophying muscle is also unknown. In the proposed project, I will test the hypotheses that a) glucocorticoids activate the atrogin-1 gene secondary to increased expression and activity of C/EBP and p300; and b) glucocorticoid-induced C/EBP-atrogin-1 gene activation cascade is at least in part responsible for muscle wasting. The project is important because it will further define the molecular regulation of glucocorticoid-related muscle wasting, such as seen in sepsis and after severe injury. The use of cultured muscle cells will allow for defining mechanisms of muscle wasting at the gene level.
