Erythropoietin acts by binding to its cell surface receptor on erythroid progenitor cells to stimulate erythrocyte production. However, erythropoietin receptor expression extends beyond hematopoietic tissue including muscle progenitor/precursor cells. Mice with erythropoietin receptor restricted to hematopoietic tissue were used to assess contributions of endogenous erythropoietin to promote skeletal myoblast proliferation and survival, and wound healing in a mouse model of cardiotoxin induced muscle injury. Compared with wild type controls, these mice had fewer skeletal muscle satellite/progenitor cells and myoblasts that do not proliferate in culture, were more susceptible to skeletal muscle injury and showed decreased muscle tension to tear. In contrast, mice with chronic elevated circulating erythropoietin had more satellite cells and myoblasts with increased proliferation and survival in culture, decreased muscle injury and accelerated muscle recovery in tension to rupture. Skeletal muscle myoblasts also produced endogenous erythropoietin that increased at low oxygen tension. Erythropoietin promoted proliferation, survival and wound recovery in myoblasts via the phosphoinositide 3-kinase/AKT pathway. Therefore, endogenous and exogenous erythropoietin contribute to increasing satellite cell number following muscle injury, improve myoblast proliferation and survival, and promote repair and regeneration in this mouse induced muscle injury model independent of its effect on erythrocyte production.

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