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Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart.
Circ Res. 2010 Jun 11; 106(11):1722-30.CircR

Abstract

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.

Authors+Show Affiliations

Duke University Medical Center , 0570 CR II Building White Zone, 200 Trent Dr, Durham NC 27710, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20395592

Citation

Carraway, Martha S., et al. "Erythropoietin Activates Mitochondrial Biogenesis and Couples Red Cell Mass to Mitochondrial Mass in the Heart." Circulation Research, vol. 106, no. 11, 2010, pp. 1722-30.
Carraway MS, Suliman HB, Jones WS, et al. Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart. Circ Res. 2010;106(11):1722-30.
Carraway, M. S., Suliman, H. B., Jones, W. S., Chen, C. W., Babiker, A., & Piantadosi, C. A. (2010). Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart. Circulation Research, 106(11), 1722-30. https://doi.org/10.1161/CIRCRESAHA.109.214353
Carraway MS, et al. Erythropoietin Activates Mitochondrial Biogenesis and Couples Red Cell Mass to Mitochondrial Mass in the Heart. Circ Res. 2010 Jun 11;106(11):1722-30. PubMed PMID: 20395592.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart. AU - Carraway,Martha S, AU - Suliman,Hagir B, AU - Jones,W Schuyler, AU - Chen,Chien-Wen, AU - Babiker,Abdelwahid, AU - Piantadosi,Claude A, Y1 - 2010/04/15/ PY - 2010/4/17/entrez PY - 2010/4/17/pubmed PY - 2010/7/10/medline SP - 1722 EP - 30 JF - Circulation research JO - Circ. Res. VL - 106 IS - 11 N2 - 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. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/20395592/Erythropoietin_activates_mitochondrial_biogenesis_and_couples_red_cell_mass_to_mitochondrial_mass_in_the_heart_ L2 - http://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.109.214353?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -