Erythropoietin is a cytokine required for red blood cell formation. Erythropoietin receptor expression is not restricted to hematopoietic cells and erythropoietin activity extends beyond blood and includes neural protection and cardiac protection demonstrated in select animal models. Using the erythropoietin receptor null mouse that develops a lethal embryonic anemia, we demonstrated that erythropoietin is required for normal endocardium and myocardium development. We also observed erythropoietin receptor expressed on skeletal muscle satellite cells. Erythropoietin stimulates myoblast proliferation and modifies expression of MyoD and myogenin transcription factors to delay cell differentiation and fusion to myotubes. Erythropoietin response is lost with down regulation of its receptor after skeletal muscle differentiation. We test the hypothesis that erythropoietin administration or up regulation of its receptor on myoblasts can contribute to muscle maintenance and/or repair. Specifically we examine erythropoietin protection in myocardial ischemia-reperfusion injury, in myoblast survival in skeletal muscle and in skeletal muscle wound healing. ? We found that in a mouse model for myocardial ischemia-reperfusion injury, erythropoietin administration significantly reduced infarct size. Erythropoietin receptor is expressed on endothelial and cardiac myocytes and an animal model was created with erythropoietin receptor restricted to hematopoietic and endothelial cells to examine cell specific response. Erythropoietin cardioprotection in this animal model is in progress. ? Myoblast transplantation for the treatment of myopathies has the potential to retard or stop muscle degeneration. We identified erythropoietin receptor expression on primitive/early myoblasts as well as more mature myoblasts isolated from mouse skeletal muscle. Erythropoietin stimulation of primary myoblasts decreased apoptosis associated with inflammatory cytokine treatment. Forced expression of erythropoietin receptor provides further protection with erythropoietin treatment. Transplantation of myoblasts into mice is being conducted to determine the ability of erythropoietin treatment to increase donor cell survival. ? In culture, we observed that erythropoietin protected myoblasts from hypoxic stress as well as inflammatory cytokines, suggesting a potential for erythropoietin activity in skeletal muscle repair. The potential of erythropoietin to influence wound healing of skeletal muscle or myoblast survival is being evaluated in a mouse model system of mechanical or toxic injury.? These studies address the role of erythropoietin in muscle maintenance and repair. Experiments are designed to elucidate regulatory mechanisms that determine endogenous erythropoietin receptor expression in myogenic cells, to reveal the nature of erythropoietin myoprotection and to illustrate the potential utility of erythropoietin administration in myoblast transplantation. The ability of erythropoietin to stimulate muscle progenitor cells demonstrates its potential to activate proliferation and/or act as a survival factor to prevent apoptosis in multi-organ systems, an activity that is closely linked to the presence and level of receptor expression.
| Jia, Yi; Warin, Renaud; Yu, Xiaobing et al. (2009) Erythropoietin signaling promotes transplanted progenitor cell survival. FASEB J 23:3089-99 |
| Noguchi, Constance Tom (2008) Where the Epo cells are. Blood 111:4836-7 |
| Cokic, Vladan P; Beleslin-Cokic, Bojana B; Noguchi, Constance T et al. (2007) Hydroxyurea increases eNOS protein levels through inhibition of proteasome activity. Nitric Oxide 16:371-8 |
