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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

Treatment of septic rats with curcumin inhibits NF-κB/p65 activity in the extensor digitorum longus muscle. Curcumin (600 mg/kg) or vehicle (control) was administered intraperitoneally 1 hour before CLP or sham-operation and muscles were harvested 4 hours later. Muscles from septic rats were used for determination of (a) p65 activity and (b) p-p65 levels in the nuclear fraction. (c) Muscles from sham-operated rats were used for measurement of p65 activity. Muscles from 2–3 rats were pooled for each measurement. Results are means ± SEM with n = 4 for each group and are expressed as % of control. *P < .05 versus control by Student’s t-test.
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fig4: Treatment of septic rats with curcumin inhibits NF-κB/p65 activity in the extensor digitorum longus muscle. Curcumin (600 mg/kg) or vehicle (control) was administered intraperitoneally 1 hour before CLP or sham-operation and muscles were harvested 4 hours later. Muscles from septic rats were used for determination of (a) p65 activity and (b) p-p65 levels in the nuclear fraction. (c) Muscles from sham-operated rats were used for measurement of p65 activity. Muscles from 2–3 rats were pooled for each measurement. Results are means ± SEM with n = 4 for each group and are expressed as % of control. *P < .05 versus control by Student’s t-test.

Mentions: One of the mechanisms by which curcumin has been reported to exert anti-inflammatory and protective effects is inhibition of NF-κB activity [20, 21]. We reported previously that NF-κB DNA binding activity in skeletal muscle was increased after CLP in rats and that this effect of sepsis was particularly pronounced during the early phase of sepsis (4 hours after CLP) [14]. Here, we examined the effect of curcumin (600 mg/kg administered 1 hour before CLP) on NF-κB activity in muscle 4 hours after CLP and found that NF-κB activity, determined as p65 activity in the nuclear fraction, was reduced by approximately 30% in septic rats treated with curcumin (Figure 4(a)). The inhibitory effect on NF-κBactivity was further illustrated by reduced nuclear levels of phosphorylated p65 in curcumin-treated septic rats (Figure 4(b)). Previous studies providedevidence that phosphorylation of Ser 536 was associated with activation of p65 in endotoxemia [37]. In contrast, curcumin treatment of sham-operated rats did not significantly influence nuclear p65 activity (Figure 4(c)).


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 septic rats with curcumin inhibits NF-κB/p65 activity in the extensor digitorum longus muscle. Curcumin (600 mg/kg) or vehicle (control) was administered intraperitoneally 1 hour before CLP or sham-operation and muscles were harvested 4 hours later. Muscles from septic rats were used for determination of (a) p65 activity and (b) p-p65 levels in the nuclear fraction. (c) Muscles from sham-operated rats were used for measurement of p65 activity. Muscles from 2–3 rats were pooled for each measurement. Results are means ± SEM with n = 4 for each group and are expressed as % of control. *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

fig4: Treatment of septic rats with curcumin inhibits NF-κB/p65 activity in the extensor digitorum longus muscle. Curcumin (600 mg/kg) or vehicle (control) was administered intraperitoneally 1 hour before CLP or sham-operation and muscles were harvested 4 hours later. Muscles from septic rats were used for determination of (a) p65 activity and (b) p-p65 levels in the nuclear fraction. (c) Muscles from sham-operated rats were used for measurement of p65 activity. Muscles from 2–3 rats were pooled for each measurement. Results are means ± SEM with n = 4 for each group and are expressed as % of control. *P < .05 versus control by Student’s t-test.
Mentions: One of the mechanisms by which curcumin has been reported to exert anti-inflammatory and protective effects is inhibition of NF-κB activity [20, 21]. We reported previously that NF-κB DNA binding activity in skeletal muscle was increased after CLP in rats and that this effect of sepsis was particularly pronounced during the early phase of sepsis (4 hours after CLP) [14]. Here, we examined the effect of curcumin (600 mg/kg administered 1 hour before CLP) on NF-κB activity in muscle 4 hours after CLP and found that NF-κB activity, determined as p65 activity in the nuclear fraction, was reduced by approximately 30% in septic rats treated with curcumin (Figure 4(a)). The inhibitory effect on NF-κBactivity was further illustrated by reduced nuclear levels of phosphorylated p65 in curcumin-treated septic rats (Figure 4(b)). Previous studies providedevidence that phosphorylation of Ser 536 was associated with activation of p65 in endotoxemia [37]. In contrast, curcumin treatment of sham-operated rats did not significantly influence nuclear p65 activity (Figure 4(c)).

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