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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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Curcumin inhibits sepsis-induced muscle proteolysis. (a) Rats were treated with different doses of curcumin and the inhibition of muscle protein breakdown in septic rats was calculated as percent inhibition of tyrosine release from muscles of curcumin-treated septic rats compared with tyrosine release from muscles of vehicle-treated septic rats. Results are from experiments in which 8 septic rats treated with vehicle and 8 septic rats treated with curcumin were studied for each total dose of curcuminindicated in the figure. (b) 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). Protein breakdown rates were determined in incubated extensor digitorum longus muscles 16 hours after sham-operation or CLP by measuring net release of tyrosine. Results are means ± SEM with n = 8 in each group. *P < .05 versus all other groups by ANOVA.
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fig1: Curcumin inhibits sepsis-induced muscle proteolysis. (a) Rats were treated with different doses of curcumin and the inhibition of muscle protein breakdown in septic rats was calculated as percent inhibition of tyrosine release from muscles of curcumin-treated septic rats compared with tyrosine release from muscles of vehicle-treated septic rats. Results are from experiments in which 8 septic rats treated with vehicle and 8 septic rats treated with curcumin were studied for each total dose of curcuminindicated in the figure. (b) 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). Protein breakdown rates were determined in incubated extensor digitorum longus muscles 16 hours after sham-operation or CLP by measuring net release of tyrosine. Results are means ± SEM with n = 8 in each group. *P < .05 versus all other groups by ANOVA.

Mentions: In previous reports, examining the protective effects of curcumin in skeletal muscle, the dose of the drug varied substantially, ranging from 10–20 μg/kg [23, 34] to 1.7 g/kg [22]. Studies suggest that doses as high as 2 g/kg can be given without toxic effects in rats [35, 36]. In initial experiments in the present study, we treated rats with three repeated doses of 60 μg/kg each of curcumin administered intraperitoneally. Because no improvement in muscleprotein balance was seen in those experiments, we instead used curcumin doses corresponding to the higher end of the spectrum reported previously. When rats were treated with total amounts of curcumin ranging from 400 to 1800 mg/kg divided into three doses administered intraperitonelly 1 hour before and 8 and 15 hours after sham-operation or CLP, a dose-dependent reduction of muscle protein breakdown rates was noticed in septic rats (Figure 1(a)). At the highestdose tested (three doses of 600 mg/kg), the sepsis-induced increase in muscle proteolysis was abolished (Figure 1(b)). Interestingly, the same dose of curcumin did not influence protein degradation in muscles from sham-operated rats,suggesting that curcumin specifically affected sepsis-induced muscleproteolysis without influencing basal protein breakdown.


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)

Curcumin inhibits sepsis-induced muscle proteolysis. (a) Rats were treated with different doses of curcumin and the inhibition of muscle protein breakdown in septic rats was calculated as percent inhibition of tyrosine release from muscles of curcumin-treated septic rats compared with tyrosine release from muscles of vehicle-treated septic rats. Results are from experiments in which 8 septic rats treated with vehicle and 8 septic rats treated with curcumin were studied for each total dose of curcuminindicated in the figure. (b) 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). Protein breakdown rates were determined in incubated extensor digitorum longus muscles 16 hours after sham-operation or CLP by measuring net release of tyrosine. Results are means ± SEM with n = 8 in each group. *P < .05 versus all other groups by ANOVA.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Curcumin inhibits sepsis-induced muscle proteolysis. (a) Rats were treated with different doses of curcumin and the inhibition of muscle protein breakdown in septic rats was calculated as percent inhibition of tyrosine release from muscles of curcumin-treated septic rats compared with tyrosine release from muscles of vehicle-treated septic rats. Results are from experiments in which 8 septic rats treated with vehicle and 8 septic rats treated with curcumin were studied for each total dose of curcuminindicated in the figure. (b) 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). Protein breakdown rates were determined in incubated extensor digitorum longus muscles 16 hours after sham-operation or CLP by measuring net release of tyrosine. Results are means ± SEM with n = 8 in each group. *P < .05 versus all other groups by ANOVA.
Mentions: In previous reports, examining the protective effects of curcumin in skeletal muscle, the dose of the drug varied substantially, ranging from 10–20 μg/kg [23, 34] to 1.7 g/kg [22]. Studies suggest that doses as high as 2 g/kg can be given without toxic effects in rats [35, 36]. In initial experiments in the present study, we treated rats with three repeated doses of 60 μg/kg each of curcumin administered intraperitoneally. Because no improvement in muscleprotein balance was seen in those experiments, we instead used curcumin doses corresponding to the higher end of the spectrum reported previously. When rats were treated with total amounts of curcumin ranging from 400 to 1800 mg/kg divided into three doses administered intraperitonelly 1 hour before and 8 and 15 hours after sham-operation or CLP, a dose-dependent reduction of muscle protein breakdown rates was noticed in septic rats (Figure 1(a)). At the highestdose tested (three doses of 600 mg/kg), the sepsis-induced increase in muscle proteolysis was abolished (Figure 1(b)). Interestingly, the same dose of curcumin did not influence protein degradation in muscles from sham-operated rats,suggesting that curcumin specifically affected sepsis-induced muscleproteolysis without influencing basal protein breakdown.

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