Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1beta in skeletal muscle.

Muscle wasting during sepsis is at least in part regulated by glucocorticoids and is associated with increased transcription of genes encoding the ubiquitin ligases atrogin-1 and muscle-specific RING-finger protein-1 (MuRF1). Recent studies suggest that muscle atrophy caused by denervation is associated with reduced expression of the nuclear cofactor peroxisome proliferator-activated receptor-γ coactivator (PGC)-1β and that PGC-1β may be a repressor of the atrogin-1 and MuRF1 genes. The influence of other muscle-wasting conditions on the expression of PGC-1β is not known.

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.

GSK-3beta inhibitors reduce protein degradation in muscles from septic rats and in dexamethasone-treated myotubes.

Sepsis is associated with muscle wasting, mainly reflecting increased muscle proteolysis. Recent studies suggest that inhibition of GSK-3beta activity may counteract catabolic stimuli in skeletal muscle. We tested the hypothesis that treatment of muscles from septic rats with the GSK-3beta inhibitors LiCl and TDZD-8 would reduce sepsis-induced muscle proteolysis.

Dexamethasone upregulates the expression of the nuclear cofactor p300 and its interaction with C/EBPbeta in cultured myotubes.

Muscle wasting during sepsis and other catabolic conditions is, at least in part, mediated by glucocorticoids and is associated with upregulated transcription of multiple genes in the ubiquitin-proteasome proteolytic pathway. In addition to transcription factors, nuclear cofactors, including p300, regulate gene transcription. We tested the hypothesis that glucocorticoids upregulate the expression of p300 in muscle cells.

Sepsis stimulates calpain activity in skeletal muscle by decreasing calpastatin activity but does not activate caspase-3.

We examined the influence of sepsis on the expression and activity of the calpain and caspase systems in skeletal muscle. Sepsis was induced in rats by cecal ligation and puncture (CLP). Control rats were sham operated.

Treatment of cultured myotubes with the calcium ionophore A23187 increases proteasome activity via a CaMK II-caspase-calpain-dependent mechanism.

Background: Previous studies suggest that increased ubiquitin-proteasome-dependent protein breakdown in various muscle-wasting conditions may at least in part be mediated by increased cellular calcium levels. The role of calcium in the regulation of proteasome activity, however, is not well understood.

Methods: We treated cultured L6 myotubes with the calcium ionophore A23187 or thapsigargin, substances that increase intracellular calcium levels through different mechanisms, and measured proteasome activity by determining the degradation of the fluorogenic substrate LLVY-AMC.