Subject(s)
Benzamides/therapeutic use , Blast Crisis/genetics , Eosinophilia/etiology , Leukemia, Myeloid/genetics , Lymphoma, T-Cell/genetics , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Receptor, Platelet-Derived Growth Factor beta/genetics , Sarcoma, Myeloid/genetics , Antineoplastic Agents/therapeutic use , Blast Crisis/complications , Blast Crisis/mortality , Eosinophilia/drug therapy , Eosinophilia/mortality , Follow-Up Studies , Gene Rearrangement , Humans , Imatinib Mesylate , Leukemia, Myeloid/complications , Leukemia, Myeloid/drug therapy , Leukemia, Myeloid/mortality , Lymphoma, T-Cell/complications , Lymphoma, T-Cell/drug therapy , Lymphoma, T-Cell/mortality , Oncogene Proteins, Fusion/genetics , Prognosis , Receptor, Platelet-Derived Growth Factor alpha/genetics , Sarcoma, Myeloid/complications , Sarcoma, Myeloid/drug therapy , Sarcoma, Myeloid/mortality , Survival Rate , mRNA Cleavage and Polyadenylation Factors/geneticsABSTRACT
Previous studies have suggested that an increased catabolic stage of skeletal muscle in pathological situations is mainly a reflection of ubiquitin-proteasome system-controlled proteolysis. The proteolytic mechanisms that occur after local muscle trauma are poorly defined. We investigated the effects of closed soft-tissue trauma on ubiquitin-proteasome dependent protein breakdown in rats (n = 25). The enzymatic activities of the ubiquitination and proteasome reactions were both reduced (p < 0.05) immediately after contusion of the hind limb musculus extensor digitorum longus. The same effect was observed in extracts of lung tissue from the injured animals. Cellular levels of free and protein-conjugated ubiquitin were significantly elevated upon decreased proteolytic activity. Our data support an early-state anti-proteolytic role of the ubiquitin-proteasome pathway after local injury. This further implies that there is a yet-to-be elucidated complex regulatory mechanism of muscle regeneration that involves various proteolytic systems.
ABSTRACT
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/microg; 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.
