Based on the biological significance of the ubiquitin-proteasome pathway (UPP) and its potential role during sepsis, burns and ischemia-reperfusion injury, we hypothesized that the systemic response to traumatic shock (TS) is accompanied by tissue-specific UPP alterations. Therefore, we studied tissue ubiquitin pools, chymotryptic- and tryptic-like proteasome peptidase activities and ubiquitin-protein ligation (UbPL) rates in skeletal muscle, heart, lung, liver, spleen and kidney using a clinically relevant porcine model (bilateral femur fracture/hemorrhage followed by fluid resuscitation). TS induced a systemic reduction of tissue- specific high molecular mass ubiquitin-protein conjugates (>50 kDa). Free ubiquitin was unaffected. The dynamic organ patterns of ubiquitin pools paralleled the typical physiological response to TS and resuscitation. Reduction of ubiquitin-protein conjugates was most pronounced in heart and lung (p<0.05 vs. control) and accompanied by significant increases in proteasome peptidase and UbPL activities in these organs. Unlike all other tissues, spleen proteasome peptidase and UbPL activities were significantly reduced 10 h after TS. These findings support the concept that the UPP could play an important role in regulation of cell functions during the early whole-body response to TS. The UPP might be a therapeutic target to improve the metabolic care after TS, particularly in the heart, lung, and spleen., M. B. Patel, S. A. Earle, M. Majetschak., and Obsahuje bibliografii a bibliografické odkazy
Metabolic consequences of direct muscle trauma are insufficiently defined. Their effects on the ubiquitin-proteasome pathway (UPP) of protein degradation in human skeletal muscles are as yet unknown. Thus, we investigated whether the UPP is involved in the metabolic response evoked in directly traumatized human skeletal muscles. Biopsies were obtained from contused muscles after fractures and from normal muscles during elective implant removal (control). As estimated by western blot analyses, concentrations of free ubiquitin and ubiquitin protein conjugates were similar in extracts from injured and uninjured muscles. Ubiquitin protein ligation rates were reduced after injury (1.5±0.2 vs. 1.0±0.15 fkat/μg; p=0.04). Chymotryptic-, tryptic- and caspase-like proteasome peptidase activities (total activity minus activity in the presence of proteasome inhibitors) increased significantly after trauma (p=0.04 - 0.001). Significant increases in total chymotryptic- and caspase-like activities were attributable to proteasome activation. Our results extend the possible role of the UPP in muscle wasting to direct muscle trauma. They further suggest that the effects of direct mechanical trauma are not limited to the proteasome and imply that ubiquitin protein ligase systems are also involved. Based on the potential role of the UPP in systemic diseases, it might also be a therapeutic target to influence muscle loss in critically ill blunt trauma patients, in which large proportions of muscle are exposed to direct trauma. and Obsahuje bibliografii a bibliografické odkazy