The NF‐κB Inhibitor Curcumin Blocks Sepsis‐Induced Muscle Proteolysis

Abstract

We tested the hypothesis that treatment of rats with curcumin prevents sepsis‐induced muscle protein degradation. In addition, we determined the influence of curcumin on different proteolytic pathways that are activated in septic muscle (i.e., ubiquitin‐proteasome‐, calpain‐, and cathepsin L‐dependent proteolysis) and examined the role of NF‐κB and p38/MAP kinase inactivation in curcumin‐induced inhibition of muscle protein breakdown. Rats were made septic by cecal ligation and puncture or were sham‐operated. Groups of rats were treated with three intraperitoneal doses (600 mg/kg) of curcumin or corresponding volumes of solvent. Protein breakdown rates were measured as release of tyrosine from incubated extensor digitorum longus muscles. Treatment with curcumin prevented sepsis‐induced increase in muscle protein breakdown. Surprisingly, the upregulated expression of the ubiquitin ligases atrogin‐1 and MuRF1 was not influenced by curcumin. When muscles from septic rats were treated with curcumin in vitro, proteasome‐, calpain‐, and cathepsin L‐dependent protein breakdown rates were reduced, and nuclear NF‐κB/p65 expression and activity as well as levels of phosphorylated (activated) p38 were decreased. Results suggest that sepsis‐induced muscle proteolysis can be blocked by curcumin and that this effect may, at least in part, be caused by inhibited NF‐κB and p38 activities. The results also suggest that there is not an absolute correlation between changes in muscle protein breakdown rates and changes in atrogin‐1 and MuRF1 expression during treatment of muscle wasting.