title: Endogenous erythropoietin signaling facilitates skeletal muscle repair and recovery following pharmacologically induced damage.
abstract: Erythropoietin acts by binding to its cell surface receptor on erythroid progenitor cells to stimulate erythrocyte production. Erythropoietin receptor expression in nonhematopoietic tissue, including skeletal muscle progenitor cells, raises the possibility of a role for erythropoietin beyond erythropoiesis. 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 Pax-7(+) satellite cells and myoblasts that do not proliferate in culture, were more susceptible to skeletal muscle injury and reduced maximum load tolerated by isolated muscle. In contrast, mice with chronic elevated circulating erythropoietin had more Pax-7(+) satellite cells and myoblasts with increased proliferation and survival in culture, decreased muscle injury, and accelerated recovery of maximum load tolerated by isolated muscle. Skeletal muscle myoblasts also produced endogenous erythropoietin that increased at low O(2). 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.
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1822, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jia
authors.forename: Norio
authors.initials: N
authors.lastname: Suzuki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004921:Erythropoietin / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D005260:Female; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000293:injuries* / Q000503:physiopathology*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000502:physiology; D051763:PAX7 Transcription Factor / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
chemical_list: C554270:EPO protein, human; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D051057:Proto-Oncogene Proteins c-akt