Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts

Erythropoietin (Epo) is required for the production of mature red blood cel ls. The requirement for Epo and its receptor (EpoR) for normal heart develo pment and the response of vascular endothelium and cells of neural origin t o Epo provide evidence that the function of Epo as a growth factor or cytok ine to protect cells from apoptosis extends beyond the hematopoietic lineag e. me now report that the EpoR is expressed on myoblasts and can mediate a biological response of these cells to treatment with Epo. Primary murine sa tellite cells and myoblast C2C12 cells, both of which express endogenous Ep oR, exhibit a proliferative response to Epo and a marked decrease in termin al differentiation to form myotubes. me also observed that Epo stimulation activates Jak2/Stat5 signal transduction and increases cytoplasmic calcium, which is dependent on tyrosine phosphorylation. In erythroid progenitor ce lls, Epo stimulates induction of transcription factor GATA-1 and EpoR; in C 2C12 cells, GATA-3 and EpoR expression are induced. The decrease in differe ntiation of C2C12 cells is concomitant with an increase in Myf-5 and MyoD e xpression and inhibition of myogenin induction during differentiation, alte ring the pattern of expression of the MyoD family of transcription factors during muscle differentiation. These data suggest that, rather than acting in an instructive or specific mode for differentiation, Epo can stimulate p roliferation of myoblasts to expand the progenitor population during differ entiation and may have a potential role in muscle development or repair.