Limits...
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.

Show MeSH

Related in: MedlinePlus

(a) Western blot analysis of phosphorylated and total p38 in septic extensor digitorum longus muscles incubated for 2 hours in the absence (control) or presence of 100 μM curcumin. Muscle levels of α-tubulin were determined for loading control. Similar results were observed in four repeated experiments. (b) Quantification of p-p38 Western blots by densitometry. Results are means ± SEM with n = 4 in each group. *P < .05 versus control by Student’s t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2279164&req=5

fig8: (a) Western blot analysis of phosphorylated and total p38 in septic extensor digitorum longus muscles incubated for 2 hours in the absence (control) or presence of 100 μM curcumin. Muscle levels of α-tubulin were determined for loading control. Similar results were observed in four repeated experiments. (b) Quantification of p-p38 Western blots by densitometry. Results are means ± SEM with n = 4 in each group. *P < .05 versus control by Student’s t-test.

Mentions: In addition to decreased NF-κB activity, another mechanism that may be involved in the effects of curcumin is inhibition of p38 kinase activity [26, 44]. In order to test the potential role of this mechanism, the levels of phosphorylated (activated) p38 (p-p38) were determined in muscles from septic rats incubated in the presence of curcumin. Treatment ofseptic muscles with curcumin resulted in reduced tissue levels of p-p38,consistent with inhibited p38 activity (Figures 8(a) and 8(b)). The potential role of p38 in the regulation of muscle proteolysis was further tested by treating incubated muscles from septic rats with the p38 inhibitor SB202190. This drug specifically reduces the activity of p38γ, the predominant p38 isoform in skeletal muscle [45, 46]. Treatment of incubated muscles from septic rats with 50 μM SB202190 resulted in an approximately 30% inhibition of protein breakdown (data not shown).


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)

(a) Western blot analysis of phosphorylated and total p38 in septic extensor digitorum longus muscles incubated for 2 hours in the absence (control) or presence of 100 μM curcumin. Muscle levels of α-tubulin were determined for loading control. Similar results were observed in four repeated experiments. (b) Quantification of p-p38 Western blots by densitometry. Results are means ± SEM with n = 4 in each group. *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

fig8: (a) Western blot analysis of phosphorylated and total p38 in septic extensor digitorum longus muscles incubated for 2 hours in the absence (control) or presence of 100 μM curcumin. Muscle levels of α-tubulin were determined for loading control. Similar results were observed in four repeated experiments. (b) Quantification of p-p38 Western blots by densitometry. Results are means ± SEM with n = 4 in each group. *P < .05 versus control by Student’s t-test.
Mentions: In addition to decreased NF-κB activity, another mechanism that may be involved in the effects of curcumin is inhibition of p38 kinase activity [26, 44]. In order to test the potential role of this mechanism, the levels of phosphorylated (activated) p38 (p-p38) were determined in muscles from septic rats incubated in the presence of curcumin. Treatment ofseptic muscles with curcumin resulted in reduced tissue levels of p-p38,consistent with inhibited p38 activity (Figures 8(a) and 8(b)). The potential role of p38 in the regulation of muscle proteolysis was further tested by treating incubated muscles from septic rats with the p38 inhibitor SB202190. This drug specifically reduces the activity of p38γ, the predominant p38 isoform in skeletal muscle [45, 46]. Treatment of incubated muscles from septic rats with 50 μM SB202190 resulted in an approximately 30% inhibition of protein breakdown (data not shown).

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