Apart from its hematopoietic effect, erythropoietin (EPO) is known as pleiotropic cytokine with anti-inflammatory and antiapoptotic properties. Here, we evaluated for the first time the EPO-dependent regeneration capacity in an in vivo rat model of skeletal muscle trauma. A myoblast cell line was used to study the effect of EPO on serum deprivation-induced cell apoptosis in vitro. A crush injury was performed to the left soleus muscle in 80 rats treated with either EPO or saline. Muscle recovery was assessed by analysis of contraction capacities. Intravital microscopy, BrdU/laminin double immunohistochemistry and cleaved caspase-3 immunohistochemistry of muscle tissue on days 1, 7, 14, and 42 posttrauma served for assessment of local microcirculation, tissue integrity, and cell proliferation. Serum deprivation-induced myoblast apoptosis of 23.9 AE 1.5% was reduced by EPO to 17.2 AE 0.8%. Contraction force analysis in the EPO-treated animals revealed significantly improved muscle strength with 10-20% higher values of twitch and tetanic forces over the 42-day observation period. EPO-treated muscle tissue displayed improved functional capillary density as well as reduced leukocytic response and consecutively macromolecular leakage over day 14. Concomitantly, muscle histology showed significantly increased numbers of BrdU-positive satellite cells and interstitial cells as well as slightly lower counts of cleaved caspase-3-positive interstitial cells. EPO results in faster and better regeneration of skeletal muscle tissue after severe trauma and goes along with improved microcirculation. Thus, EPO, a compound established as clinically safe, may represent a promising therapeutic option to optimize the posttraumatic course of muscle tissue healing.

The goals of this study were to develop a new intramedullary, rotation-stable locking device and evaluate it biomechanically and in vivo for maintenance of a critical size osteotomy gap in a model of conscious pseudarthrosis. In standardized osteotomized rat femora (5 mm osteotomy gap) two different rotation-and axial-stable locking devices (group pS þ cS) were tested in vitro with respect to biomechanics and compared to a control group without an additional locking device (K; n ¼ 6 for each group). For in vivo studies, 27 male Sprague Dawley rats (250-300 g) underwent a femoral defect osteotomy of critical size and were stabilized by one of the three methods (n ¼ 9 for each group). All groups were examined radiologically postoperatively, after 14 days, and after 12 weeks. In vitro testing revealed higher compression and torsional rigidities for the two locking devices (p < 0.05) compared to the control group (compression rigidity: pS ¼ 103.6 AE 13.2; cS ¼ 91.3 AE 10.9; K ¼ 52.8 AE 8.4 N/mm; torsional rigidity: pS ¼ 5.9 AE 0.9; cS ¼ 4.3 AE 1.4; K ¼ 0.4 AE 0.1 Nmm/8). In vivo, group K and pS exhibited up to two thirds wire dislocation and reduction of the osteotomy gap, while dislocation was less frequent in the cS group. Thus, the locking device with compression of the wire showed advantages in rotational and axial stability for a critically sized defect, though the osteotomy gap could not be maintained in all cases over the 12-week period. Nevertheless, our data corroborate the necessity of an internal fixation device with sufficient axial and rotational stability. ß

High susceptibility of the peripheral nerve to compression-induced ischemic injury disproves IPC in its clinical application for surgical procedures requiring prolonged tourniquet ischemia.

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.

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