title: Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart.
abstract: BACKGROUND
  Erythropoietin (EPO) is often administered to cardiac patients with anemia, particularly from chronic kidney disease, and stimulation of erythropoiesis may stabilize left ventricular and renal function by recruiting protective effects beyond the correction of anemia.
  
  
  OBJECTIVE
  We examined the hypothesis that EPO receptor (EpoR) ligand-binding, which activates endothelial NO synthase (eNOS), regulates the prosurvival program of mitochondrial biogenesis in the heart.
  
  
  RESULTS
  We investigated the effects of EPO on mitochondrial biogenesis over 14 days in healthy mice. Mice expressing a mitochondrial green fluorescent protein reporter construct demonstrated sharp increases in myocardial mitochondrial density after 3 days of EPO administration that peaked at 7 days and surpassed hepatic or renal effects and anteceded significant increases in blood hemoglobin content. Quantitatively, in wild-type mice, complex II activity, state 3 respiration, and mtDNA copy number increased significantly; also, resting energy expenditure and natural running speed improved, with no evidence of an increase in left ventricular mass index. Mechanistically, EPO activated cardiac mitochondrial biogenesis by enhancement of nuclear respiratory factor-1, PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator 1alpha), and mitochondrial transcription factor-A gene expression in wild-type but not in eNOS(-/-) or protein kinase B (Akt1)(-/-) mice. EpoR was required, because EpoR silencing in cardiomyocytes blocked EPO-mediated nuclear translocation of nuclear respiratory factor-1.
  
  
  CONCLUSIONS
  These findings support a new physiological and protective role for EPO, acting through its cell surface receptor and eNOS-Akt1 signal transduction, in matching cardiac mitochondrial mass to the convective O(2) transport capacity as erythrocyte mass expands.
authors.affiliation: Duke University Medical Center , 0570 CR II Building White Zone, 200 Trent Dr, Durham NC 27710, USA.
authors.forename: Martha S
authors.initials: MS
authors.lastname: Carraway
authors.forename: Hagir B
authors.initials: HB
authors.lastname: Suliman
authors.forename: W Schuyler
authors.initials: WS
authors.lastname: Jones
authors.forename: Chien-Wen
authors.initials: CW
authors.lastname: Chen
authors.forename: Abdelwahid
authors.initials: A
authors.lastname: Babiker
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival; D004272:DNA, Mitochondrial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004452:Echocardiography; D042963:Electron Transport Complex II / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics; D034622:RNA Interference; D017467:Receptors, Erythropoietin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006454:Hemoglobins; D024101:Mitochondrial Proteins; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D004921:Erythropoietin; D049452:Green Fluorescent Proteins; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D042963:Electron Transport Complex II; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
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