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-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.
Highlights
Increased breakdown of muscle proteins, in particular the myofibrillar proteins actin and myosin, is a common metabolic consequence of sepsis and other critical illness, resulting in muscle wasting, weakness, and fatigue [1, 2]
Further evidence for a role of NF-κB in muscle atrophy was found in a recent study in which muscle-specific overexpression of activated IkB kinase β (IKKβ) in mice resulted in phosphorylation and degradation of the inhibitory protein IkBα, activation of NF-κB, increased proteasome-dependent protein breakdown, and muscle atrophy [17]
We found in previous reports that cecal ligation and puncture (CLP) in rats was associated with an early activation of NF-κB in skeletal muscle [14], accelerated ubiquitin-proteasome-dependent muscle proteolysis [28], and a substantial increase in atrogin-1 and MuRF1 mRNA levels [12]
Summary
Increased breakdown of muscle proteins, in particular the myofibrillar proteins actin and myosin, is a common metabolic consequence of sepsis and other critical illness, resulting in muscle wasting, weakness, and fatigue [1, 2]. Calpain- and cathepsin L-dependent proteolytic mechanisms are activated in atrophying muscle [3,4,5,6], ubiquitin-proteasome-dependent proteolysis plays a important role in muscle wasting [7,8,9]. The molecular regulation of muscle wasting is complex and involves activation of various transcription factors and nuclear cofactors regulating genes in different proteolytic pathways reviewed in [13]. Further evidence for a role of NF-κB in muscle atrophy was found in a recent study in which muscle-specific overexpression of activated IkB kinase β (IKKβ) in mice resulted in phosphorylation and degradation of the inhibitory protein IkBα, activation of NF-κB, increased proteasome-dependent protein breakdown, and muscle atrophy [17]
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