ObjectiveTo investigate the mechanism of muscle protein breakdown under endotoxemia condition.DesignRandomized, controlled, animal experiment in a hospital institute.SettingExperimental laboratory.InterventionEither saline or endotoxin (Escherichia coliO55B5, 10 mg/kg) were administered into the peritoneal cavity in rats.Measurements and Main ResultsThe rate of total protein breakdown was increased by 29% and 61% in extensor digitorum longus muscle at 2 hrs and 6 hrs, whereas the myofibrillar proteolytic rate was increased by 155%, 222%, and 40% at 2 hrs, 6 hrs, and 12 hrs, respectively, in the endotoxin treatment group compared with that of the pair-fed normal control group. Meanwhile, compared with the normal control group, the level of 2.4-kilobase (kb) messenger RNA (mRNA) for ubiquitin in extensor digitorum longus muscle in rats was increased by 153% and 470% at 2 hrs and 6 hrs. There were 87% and 117% increases in 1.2-kb mRNA for E2-14K, and 89% and 168% increase in RC2 mRNA expression in extensor digitorum longus muscle in endotoxemic rats than normal control rats at 2 hrs and 6 hrs after injection of endotoxin peritoneally. The tumor necrosis factor-&agr; and interleukin-6 concentrations in rat plasma progressively increased after endotoxin treatment, but tumor necrosis factor-&agr; peaked at the 2-hr time point, whereas interleukin-6 peaked at 12 hrs. Endotoxin administration resulted in a marked increase in endotoxin level at 2 hrs and 6 hrs. No significant change was observed in soleus muscle after endotoxin injection. A significantly positive correlation was found between the net release of 3-methylhistidine and respective values of endotoxin, intensity of mRNA expression of 2.-kb ubiquitin, 1.2-kb E2-14K, and subunit RC2 in extensor digitorum longus muscle (r= .9882, .9731, .9653, .9814,p< .05). However, no significant correlation was seen between tumor necrosis factor-&agr; or interleukin-6 and respective values of 3-methylhistidine, mRNA expression of 2.4-kb ubiquitin, 1.2-kb E2-14K, and subunit RC2 (r= .3580, .4521, .5277, .4931,p> .05;r= .3950, .1767, .2136, .2519,p> .05, respectively.) in soleus muscle.ConclusionsEndotoxemia can induce enhancement of skeletal muscle protein breakdown, mainly involving myofibrillar protein and white, fast-twitch extensor digitorum longus muscle. Ubiquitin-proteasome proteolytic pathway plays an important and major role in skeletal muscle proteolysis. Endotoxin, tumor necrosis factor-&agr;, and interleukin-6 can directly or indirectly regulate muscle protein breakdown.