scholarly journals The NF-κB Inhibitor Curcumin Blocks Sepsis-Induced Muscle Proteolysis

2008 ◽  
Vol 2008 ◽  
pp. 1-13 ◽  
Author(s):  
Vitaliy Poylin ◽  
Moin U. Fareed ◽  
Patrick O'Neal ◽  
Nima Alamdari ◽  
Natasha Reilly ◽  
...  
Keyword(s):  
Muscle Protein ◽  
Cathepsin L ◽  
Cecal Ligation ◽  
P38 Map Kinase ◽  
Protein Breakdown ◽  
Muscle Protein Breakdown ◽  
Breakdown Rates ◽  
Dependent Protein ◽  
Absolute Correlation

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-κB 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-κB/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-κB 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.

Treatment of rats with calpain inhibitors prevents sepsis-induced muscle proteolysis independent of atrogin-1/MAFbx and MuRF1 expression

2006 ◽  
Vol 290 (6) ◽  
pp. R1589-R1597 ◽  
Author(s):  
Moin U. Fareed ◽  
Amy R. Evenson ◽  
Wei Wei ◽  
Michael Menconi ◽  
Vitaliy Poylin ◽  
...  
Keyword(s):  
Muscle Wasting ◽  
Muscle Protein ◽  
Cecal Ligation ◽  
26S Proteasome ◽  
Calpain Inhibitor ◽  
Protein Breakdown ◽  
Calpain Activity ◽  
Breakdown Rates ◽  
Calpain Inhibitors

Muscle wasting in sepsis is a significant clinical problem because it results in muscle weakness and fatigue that may delay ambulation and increase the risk for thromboembolic and pulmonary complications. Treatments aimed at preventing or reducing muscle wasting in sepsis, therefore, may have important clinical implications. Recent studies suggest that sepsis-induced muscle proteolysis may be initiated by calpain-dependent release of myofilaments from the sarcomere, followed by ubiquitination and degradation of the myofilaments by the 26S proteasome. In the present experiments, treatment of rats with one of the calpain inhibitors calpeptin or BN82270 inhibited protein breakdown in muscles from rats made septic by cecal ligation and puncture. The inhibition of protein breakdown was not accompanied by reduced expression of the ubiquitin ligases atrogin-1/MAFbx and MuRF1, suggesting that the ubiquitin-proteasome system is regulated independent of the calpain system in septic muscle. When incubated muscles were treated in vitro with calpain inhibitor, protein breakdown rates and calpain activity were reduced, consistent with a direct effect in skeletal muscle. Additional experiments suggested that the effects of BN82270 on muscle protein breakdown may, in part, reflect inhibited cathepsin L activity, in addition to inhibited calpain activity. When cultured myoblasts were transfected with a plasmid expressing the endogenous calpain inhibitor calpastatin, the increased protein breakdown rates in dexamethasone-treated myoblasts were reduced, supporting a role of calpain activity in atrophying muscle. The present results suggest that treatment with calpain inhibitors may prevent sepsis-induced muscle wasting.

Sepsis in mice stimulates muscle proteolysis in the absence of IL-6

1998 ◽  
Vol 275 (6) ◽  
pp. R1983-R1991 ◽  
Author(s):  
Arthur Williams ◽  
Jing Jing Wang ◽  
Li Wang ◽  
Xiaoyan Sun ◽  
Josef E. Fischer ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Muscle Protein ◽  
Mrna Levels ◽  
Protein Breakdown ◽  
Wild Type ◽  
Dot Blot ◽  
Muscle Protein Breakdown ◽  
L6 Myotubes ◽  
Identical Response ◽  
Breakdown Rates

We tested the role of interleukin-6 (IL-6) in sepsis-induced muscle proteolysis by determining ubiquitin mRNA levels and protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated IL-6 knockout and wild-type mice. In addition, the effect of treatment of mice with human recombinant IL-6 on muscle protein breakdown rates was determined. Finally, protein breakdown rates were measured in myotubes treated for up to 48 h with different concentrations of IL-6. Sepsis in wild-type mice resulted in an approximately ninefold increase in plasma IL-6 levels, whereas IL-6 was not detectable in plasma of sham-operated or septic IL-6 knockout mice. Total and myofibrillar muscle protein breakdown rates were increased by ∼30% and threefold, respectively, in septic IL-6 wild-type mice with an almost identical response noted in septic IL-6 knockout mice. Ubiquitin mRNA levels determined by dot blot analysis were increased during sepsis in muscles from both IL-6 knockout and wild-type mice, although the increase was less pronounced in IL-6 knockout than in wild-type mice. Treatment of normal mice or of cultured L6 myotubes with IL-6 did not influence protein breakdown rates. The present results suggest that IL-6 does not regulate muscle proteolysis during sepsis.

Tumor necrosis factor induces skeletal muscle protein breakdown in rats

1991 ◽  
Vol 260 (5) ◽  
pp. E727-E730 ◽  
Author(s):  
M. N. Goodman
Keyword(s):  
Skeletal Muscle ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Muscle Protein ◽  
Nitrogen Excretion ◽  
Protein Breakdown ◽  
Skeletal Muscle Protein ◽  
Muscle Protein Breakdown ◽  
Necrosis Factor

The metabolic response to infection includes loss of lean tissue and increased nitrogen excretion. The loss of muscle tissue during infection results in large part from accelerated skeletal muscle protein breakdown. Recent studies suggest that macrophage-derived products secreted during infection may signal increased muscle proteolysis. To test this, in the present report the ability of interleukin (IL-1) and tumor necrosis factor (TNF) to enhance muscle proteolysis was examined. Young rats were injected intravenously with either recombinant human IL-1 or TNF. For comparison some rats were injected with bacterial endotoxin. Eight hours after each treatment, the extensor digitorum longus muscles were isolated and incubated in vitro to assess muscle proteolysis by measuring tyrosine and 3-methyl-L-histidine release by the incubated muscles. Treatment of rats with either IL-1, TNF, or endotoxin all induced fever, increased serum lactate, and reduced serum zinc levels. Despite similar metabolic changes, muscle proteolysis responded differently. As expected, endotoxin treatment enhanced muscle protein breakdown, whereas IL-1 treatment was without effect. On the other hand, TNF was effective in accelerating muscle protein breakdown. TNF addition in vitro failed to enhance muscle proteolysis by incubated muscles, suggesting that its effects may be mediated in an indirect manner; however, a direct mode of action cannot yet be ruled out. Overall, the data indicate that the acute administration of TNF can signal increased muscle proteolysis similar to that observed during infection.

scholarly journals Prostaglandin E2 does not regulate total or myofibrillar protein breakdown in incubated skeletal muscle from normal or septic rats

1990 ◽  
Vol 270 (1) ◽  
pp. 45-50 ◽  
Author(s):  
P O Hasselgren ◽  
O Zamir ◽  
J H James ◽  
J E Fischer
Keyword(s):  
Skeletal Muscle ◽  
Arachidonic Acid ◽  
Prostaglandin E2 ◽  
Plasma Levels ◽  
Muscle Protein ◽  
Myofibrillar Protein ◽  
Protein Breakdown ◽  
Muscle Protein Breakdown

The role of prostaglandins in the regulation of muscle protein breakdown is controversial. We examined the influence of arachidonic acid (5 microM), prostaglandin E2 (PGE2) (2.8 microM) and the prostaglandin-synthesis inhibitor indomethacin (3 microM) on total and myofibrillar protein breakdown in rat extensor digitorum longus and soleus muscles incubated under different conditions in vitro. In other experiments, the effects of indomethacin, administered in vivo to septic rats (3 mg/kg, injected subcutaneously twice after induction of sepsis by caecal ligation and puncture) on plasma levels and muscle release of PGE2 and on total and myofibrillar protein breakdown rates were determined. Total and myofibrillar proteolysis was assessed by measuring production by incubated muscles of tyrosine and 3-methylhistidine respectively. Arachidonic acid or PGE2 added during incubation of muscles from normal rats did not affect total or myofibrillar protein degradation under a variety of different conditions in vitro. Indomethacin inhibited muscle PGE2 production by incubated muscles from septic rats, but did not lower proteolytic rates. Administration in vivo of indomethacin did not affect total or myofibrillar muscle protein breakdown, despite effective plasma levels of indomethacin with decreased plasma PGE2 levels and inhibition of muscle PGE2 release. The present results suggest that protein breakdown in skeletal muscle of normal or septic rats is not regulated by PGE2 or other prostaglandins.

Sepsis-induced increase in muscle proteolysis is blocked by specific proteasome inhibitors

1998 ◽  
Vol 274 (1) ◽  
pp. R30-R37 ◽  
Author(s):  
Scott C. Hobler ◽  
Greg Tiao ◽  
Josef E. Fischer ◽  
John Monaco ◽  
Per-Olof Hasselgren
Keyword(s):  
Molecular Mechanisms ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Proteasome Inhibitors ◽  
Mrna Levels ◽  
Protein Breakdown ◽  
Catalytic Core ◽  
Muscle Protein Breakdown ◽  
Dependent Inhibition

Recent studies suggest that sepsis stimulates ubiquitin-dependent protein breakdown in skeletal muscle. The 20S proteasome is the catalytic core of the ubiquitin-dependent proteolytic pathway. We tested the effects in vitro of the proteasome inhibitors N-acetyl-l-leucinyl-l-leucinal-l-norleucinal (LLnL) and lactacystin on protein breakdown in incubated muscles from septic rats. LLnL resulted in a dose- and time-dependent inhibition of protein breakdown in muscles from septic rats. Lactacystin blocked both total and myofibrillar muscle protein breakdown. In addition to inhibiting protein breakdown, LLnL reduced muscle protein synthesis and increased ubiquitin mRNA levels, probably reflecting inhibited proteasome-associated ribonuclease activity. Inhibited muscle protein breakdown caused by LLnL or lactacystin supports the concept that the ubiquitin-proteasome pathway plays a central role in sepsis-induced muscle proteolysis. The results suggest that muscle catabolism during sepsis may be inhibited by targeting specific molecular mechanisms of muscle proteolysis.

Effects of elevated temperature on protein breakdown in muscles from septic rats

1990 ◽  
Vol 258 (4) ◽  
pp. C589-C592 ◽  
Author(s):  
M. Hall-Angeras ◽  
U. Angeras ◽  
P. O. Hasselgren ◽  
J. E. Fischer
Keyword(s):  
Protein Synthesis ◽  
High Temperature ◽  
Elevated Temperature ◽  
Muscle Protein ◽  
Cecal Ligation ◽  
Myofibrillar Protein ◽  
Protein Breakdown ◽  
Increased Temperature ◽  
And Control

Elevated temperature has been proposed to contribute to accelerated muscle protein degradation during fever and sepsis. The present study examined the effect of increased temperature in vitro on protein turnover in skeletal muscles from septic and control rats. Sepsis was induced by cecal ligation and puncture (CLP); control rats were sham operated. After 16 h, the extensor digitorum longus (EDL) and soleus (SOL) muscles were incubated at 37 or 40 degrees C. Protein synthesis was determined by measuring incorporation of [14C]phenylalanine into protein. Total and myofibrillar protein breakdown was assessed from release of tyrosine and 3-methylhistidine (3-MH), respectively. Total protein breakdown was increased at 40 degrees C by 15% in EDL and by 29% in SOL from control rats, whereas 3-MH release was not affected. In muscles from septic rats, total and myofibrillar protein breakdown was increased by 22 and 30%, respectively, at 40 degrees C in EDL but was not altered in SOL. Protein synthesis was unaffected by high temperature both in septic and nonseptic muscles. The present results suggest that high temperature is not the primary mechanism of increased muscle protein breakdown in sepsis because the typical response to sepsis, i.e., a predominant increase in myofibrillar protein breakdown, was not induced by elevated temperature in normal muscle. It is possible, however, that increased temperature may potentiate protein breakdown that is already stimulated by sepsis because elevated temperature increased both total and myofibrillar protein breakdown in EDL from septic rats.

Metabbolism of perfused ruminant muscle

1982 ◽  
Vol 98 (2) ◽  
pp. 307-316 ◽  
Author(s):  
B. Jane Coward ◽  
P. J. Buttery
Keyword(s):  
Amino Acids ◽  
Muscle Protein ◽  
Protein Breakdown ◽  
Muscle Protein Breakdown ◽  
Constant Rate ◽  
Net Uptake ◽  
Branched Chain ◽  
Perfusion Period ◽  
A Site

SUMMARYSubstrate and nitrogen metabolism of ruminant muscle was studied in vitro using a perfused sheep hemidiaphragm preparation. Glucose, acetate, propionate and butyrate were taken up by the perfused muscle at a constant rate over 2 h. Rate of acetoacetate uptake declined over the perfusion period. Net production of 3-hydroxybutyrate over the perfusion period was observed.Release of alanine and glycine by the perfused muscle could not be accounted for by protein breakdown, implicating muscle as a site of synthesis of these amino acids. The perfused muscle metabolized aspartate and arginine to a considerable extent, but the branched-chain amino acids only to a small extent. Only a small proportion, approximately 5%, of the alanine produced by the perfused muscle was derived from glucose.In the presence of amino acids, at twice the concentration found in plasma, and insulin, some amino acids showed a net uptake by the diaphragm but when cysteine was omitted from the perfusate, all amino acids with the exception of arginine showed a net output. Evidence was obtained that protein synthesis was reduced in the absence of cysteine. The output of Nτ methylhistidine by the preparation was much higher than could be accounted for by estimates of protein breakdown using isotope dilution techniques. These data are, however, consistent with the view that Nτ methylhistidine is not a good index of muscle protein breakdown in sheep.

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