title: The NF-kappaB 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-kappaB 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-kappaB/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-kappaB 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.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Poylin
authors.forename: Moin U
authors.initials: MU
authors.lastname: Fareed
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Neal
authors.forename: Nima
authors.initials: N
authors.lastname: Alamdari
authors.forename: Natasha
authors.initials: N
authors.lastname: Reilly
authors.forename: Michael
authors.initials: M
authors.lastname: Menconi
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Hasselgren
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010447:Peptide Hydrolases / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases; D002403:Cathepsins; D010447:Peptide Hydrolases; D002154:Calpain; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534280:Ctsl protein, rat; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin