Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart

Circ Res. 2010 Jun 11;106(11):1722-30. doi: 10.1161/CIRCRESAHA.109.214353. Epub 2010 Apr 15.


Rationale: 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.

Methods and 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Respiration / drug effects
  • Cell Survival
  • DNA, Mitochondrial / metabolism
  • DNA-Binding Proteins / metabolism
  • Echocardiography
  • Electron Transport Complex II / metabolism
  • Energy Metabolism / drug effects
  • Erythrocytes / drug effects*
  • Erythrocytes / metabolism
  • Erythropoietin / administration & dosage
  • Erythropoietin / pharmacology*
  • Green Fluorescent Proteins / biosynthesis
  • Green Fluorescent Proteins / genetics
  • Hemoglobins / metabolism
  • Humans
  • Injections, Subcutaneous
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / pathology
  • Mitochondrial Proteins / metabolism
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Nitric Oxide Synthase Type III / deficiency
  • Nitric Oxide Synthase Type III / genetics
  • Nuclear Respiratory Factor 1 / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Proto-Oncogene Proteins c-akt / deficiency
  • Proto-Oncogene Proteins c-akt / genetics
  • RNA Interference
  • Receptors, Erythropoietin / drug effects
  • Receptors, Erythropoietin / genetics
  • Receptors, Erythropoietin / metabolism
  • Recombinant Proteins
  • Signal Transduction / drug effects
  • Time Factors
  • Trans-Activators / metabolism
  • Transcription Factors / metabolism


  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Hemoglobins
  • Mitochondrial Proteins
  • Nrf1 protein, mouse
  • Nuclear Respiratory Factor 1
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Receptors, Erythropoietin
  • Recombinant Proteins
  • Trans-Activators
  • Transcription Factors
  • mitochondrial transcription factor A
  • Erythropoietin
  • Green Fluorescent Proteins
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Electron Transport Complex II
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt