Novel aspects on the regulation of muscle wasting in sepsis

Muscle wasting in sepsis is associated with increased expression of messenger RNA for several genes in the ubiquitin-proteasome proteolytic pathway, indicating that increased gene transcription is involved in the development of muscle atrophy. Here we review the influence of sepsis on the expression and activity of the transcription factors activator protein-1, nuclear factor-kappaB (NF-kappaB), and CCAAT/enhancer binding protein, as well as the nuclear cofactor p300. These transcription factors may be important for sepsis-induced muscle wasting because several of the genes in the ubiquitin-proteasome proteolytic pathway have multiple binding sites for activating protein-1, nuclear factor-kappaB, and CCAAT/enhancer binding protein in their promoter regions. In addition, the potential role of increased muscle calcium levels for sepsis-induced muscle atrophy is reviewed. Calcium may regulate several mechanisms and factors involved in muscle wasting, including the expression and activity of the calpain-calpastatin system, proteasome activity, CCAAT/enhancer binding protein transcription factors, apoptosis and glucocorticoid-mediated muscle protein breakdown. Because muscle wasting is commonly seen in patients with sepsis and has severe clinical consequences, a better understanding of mechanisms regulating sepsis-induced muscle wasting may help improve the care of patients with sepsis and other muscle-wasting conditions as well.