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The NF-kappaB inhibitor curcumin blocks sepsis-induced muscle proteolysis.

Poylin V, Fareed MU, O'Neal P, Alamdari N, Reilly N, Menconi M, Hasselgren PO - Mediators Inflamm. (2008)

Bottom Line: Protein breakdown rates were measured as release of tyrosine from incubated extensor digitorum longus muscles.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

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.

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Related in: MedlinePlus

Sepsis-induced expression of atrogin-1 in extensor digitorum longus muscles is not influenced by curcumin. Sham-operated and septic rats were treated with vehicle (control) or curcumin (total dose 1800 mg/kg divided into three equal doses administered intraperitoneally 1 hour before and 8 and 15 hours after sham-operation or CLP). Muscles were harvested 16 hours after sham-operation or CLP for (a) atrogin-1 mRNA levels determined by real-time PCR and (b) atrogin-1 protein levels determined by Western blotting. In panel (b), a representative Western blot is shown in the upper portion and results from densitometric quantifications are shown in the lower portion of the figure. Results are means ± SEM with n = 8 in each group. AU: arbitrary units. *P < .05 versus corresponding sham group by ANOVA.
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fig2: Sepsis-induced expression of atrogin-1 in extensor digitorum longus muscles is not influenced by curcumin. Sham-operated and septic rats were treated with vehicle (control) or curcumin (total dose 1800 mg/kg divided into three equal doses administered intraperitoneally 1 hour before and 8 and 15 hours after sham-operation or CLP). Muscles were harvested 16 hours after sham-operation or CLP for (a) atrogin-1 mRNA levels determined by real-time PCR and (b) atrogin-1 protein levels determined by Western blotting. In panel (b), a representative Western blot is shown in the upper portion and results from densitometric quantifications are shown in the lower portion of the figure. Results are means ± SEM with n = 8 in each group. AU: arbitrary units. *P < .05 versus corresponding sham group by ANOVA.

Mentions: Muscle wasting during sepsis and other catabolic conditions is typically associated with upregulated expression of several components of the ubiquitin-proetasome proteolytic pathway, in particular the ubiquitin ligases atrogin-1 and MuRF1 [10–12]. In the current study, mRNA levels for atrogin-1 and MuRF1 in musclesfrom septic rats were increased 7 and 9 folds, respectively, above the levels in muscles from sham-operated rats (Figures 2(a) and 3(a)). The increase in mRNA levels was accompanied by increased atrogin-1 and MuRF1 protein levels as determined by Western blotting (Figures 2(b) and 3(b)). Surprisingly, the sepsis-induced increase in atrogin-1 and MuRF1 expression was not influenced by curcumin administered at the same dose that blocked the sepsis-induced increase in muscle proteolysis (three doses of 600 mg/kg).


The NF-kappaB inhibitor curcumin blocks sepsis-induced muscle proteolysis.

Poylin V, Fareed MU, O'Neal P, Alamdari N, Reilly N, Menconi M, Hasselgren PO - Mediators Inflamm. (2008)

Sepsis-induced expression of atrogin-1 in extensor digitorum longus muscles is not influenced by curcumin. Sham-operated and septic rats were treated with vehicle (control) or curcumin (total dose 1800 mg/kg divided into three equal doses administered intraperitoneally 1 hour before and 8 and 15 hours after sham-operation or CLP). Muscles were harvested 16 hours after sham-operation or CLP for (a) atrogin-1 mRNA levels determined by real-time PCR and (b) atrogin-1 protein levels determined by Western blotting. In panel (b), a representative Western blot is shown in the upper portion and results from densitometric quantifications are shown in the lower portion of the figure. Results are means ± SEM with n = 8 in each group. AU: arbitrary units. *P < .05 versus corresponding sham group by ANOVA.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2279164&req=5

fig2: Sepsis-induced expression of atrogin-1 in extensor digitorum longus muscles is not influenced by curcumin. Sham-operated and septic rats were treated with vehicle (control) or curcumin (total dose 1800 mg/kg divided into three equal doses administered intraperitoneally 1 hour before and 8 and 15 hours after sham-operation or CLP). Muscles were harvested 16 hours after sham-operation or CLP for (a) atrogin-1 mRNA levels determined by real-time PCR and (b) atrogin-1 protein levels determined by Western blotting. In panel (b), a representative Western blot is shown in the upper portion and results from densitometric quantifications are shown in the lower portion of the figure. Results are means ± SEM with n = 8 in each group. AU: arbitrary units. *P < .05 versus corresponding sham group by ANOVA.
Mentions: Muscle wasting during sepsis and other catabolic conditions is typically associated with upregulated expression of several components of the ubiquitin-proetasome proteolytic pathway, in particular the ubiquitin ligases atrogin-1 and MuRF1 [10–12]. In the current study, mRNA levels for atrogin-1 and MuRF1 in musclesfrom septic rats were increased 7 and 9 folds, respectively, above the levels in muscles from sham-operated rats (Figures 2(a) and 3(a)). The increase in mRNA levels was accompanied by increased atrogin-1 and MuRF1 protein levels as determined by Western blotting (Figures 2(b) and 3(b)). Surprisingly, the sepsis-induced increase in atrogin-1 and MuRF1 expression was not influenced by curcumin administered at the same dose that blocked the sepsis-induced increase in muscle proteolysis (three doses of 600 mg/kg).

Bottom Line: Protein breakdown rates were measured as release of tyrosine from incubated extensor digitorum longus muscles.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

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.

Show MeSH
Related in: MedlinePlus