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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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Treatment of incubated muscles from septic rats with curcumin inhibits 20S proteasome and calpain activity but does not influence cathepsin L activity. Extensor digitorum longus muscles were harvested from rats 16 hours after CLP and incubated for 2 hours in the absenceor presence of curcumin (100 μM) followed by measurement of (a) 20S proteasome activity, (b) calpain activity, and (c) cathepsin L activity as described in Section 2. Results are means ± SEM with n = 6 in each group. FU: fluorogenic units. *P < .05 versus control by Student’s t-test.
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fig6: Treatment of incubated muscles from septic rats with curcumin inhibits 20S proteasome and calpain activity but does not influence cathepsin L activity. Extensor digitorum longus muscles were harvested from rats 16 hours after CLP and incubated for 2 hours in the absenceor presence of curcumin (100 μM) followed by measurement of (a) 20S proteasome activity, (b) calpain activity, and (c) cathepsin L activity as described in Section 2. Results are means ± SEM with n = 6 in each group. FU: fluorogenic units. *P < .05 versus control by Student’s t-test.

Mentions: The influence of curcumin on individual proteolytic pathways is not known from previous studies. In order to assess the effects of curcumin on proteasomal protein degradation, incubated muscles from septic rats were treated with 100 μM of the specific proteaosme inhibitor β-lactone [40] in the absence or presence of 100 μM curcumin. Calculated as the portion of protein degradation that was blocked by β-lactone, the proteasome-dependent protein degradation was reduced by approximately 45% by curcumin (Table 1). In parallel experiments, treatment of incubated muscles from septic rats with curcumin reduced proteasome activity by approximately 65% (Figure 6(a)).


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)

Treatment of incubated muscles from septic rats with curcumin inhibits 20S proteasome and calpain activity but does not influence cathepsin L activity. Extensor digitorum longus muscles were harvested from rats 16 hours after CLP and incubated for 2 hours in the absenceor presence of curcumin (100 μM) followed by measurement of (a) 20S proteasome activity, (b) calpain activity, and (c) cathepsin L activity as described in Section 2. Results are means ± SEM with n = 6 in each group. FU: fluorogenic units. *P < .05 versus control by Student’s t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: Treatment of incubated muscles from septic rats with curcumin inhibits 20S proteasome and calpain activity but does not influence cathepsin L activity. Extensor digitorum longus muscles were harvested from rats 16 hours after CLP and incubated for 2 hours in the absenceor presence of curcumin (100 μM) followed by measurement of (a) 20S proteasome activity, (b) calpain activity, and (c) cathepsin L activity as described in Section 2. Results are means ± SEM with n = 6 in each group. FU: fluorogenic units. *P < .05 versus control by Student’s t-test.
Mentions: The influence of curcumin on individual proteolytic pathways is not known from previous studies. In order to assess the effects of curcumin on proteasomal protein degradation, incubated muscles from septic rats were treated with 100 μM of the specific proteaosme inhibitor β-lactone [40] in the absence or presence of 100 μM curcumin. Calculated as the portion of protein degradation that was blocked by β-lactone, the proteasome-dependent protein degradation was reduced by approximately 45% by curcumin (Table 1). In parallel experiments, treatment of incubated muscles from septic rats with curcumin reduced proteasome activity by approximately 65% (Figure 6(a)).

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