Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart.
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.
Carraway
Martha S
MS
Duke University Medical Center , 0570 CR II Building White Zone, 200 Trent Dr, Durham NC 27710, USA.
Suliman
Hagir B
HB
Jones
W Schuyler
WS
Chen
Chien-Wen
CW
Babiker
Abdelwahid
A
Piantadosi
Claude A
CA
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
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
J Biol Chem. 2006 Jan 6;281(1):324-33
16230352
J Clin Invest. 1996 May 1;97(9):2092-100
8621799
J Biol Chem. 1998 Nov 6;273(45):29923-8
9792710
Nat Clin Pract Cardiovasc Med. 2006 Oct;3(10):563-72
16990842
J Biol Chem. 2003 Oct 17;278(42):41510-8
12902348
FEBS Lett. 2001 Jun 29;500(1-2):7-11
11434917
Cardiovasc Res. 2006 Sep 1;71(4):684-94
16828072
Cardiovasc Res. 2006 Oct 1;72(1):51-9
16904088
Proc Natl Acad Sci U S A. 1990 Aug;87(15):5978-82
2165612
Clin Exp Nephrol. 2009 Apr;13(2):101-106
18670732
J Cell Sci. 2007 Jan 15;120(Pt 2):299-308
17179207
N Engl J Med. 2006 Nov 16;355(20):2085-98
17108343
J Am Diet Assoc. 1997 Oct;97(10 Suppl 2):S154-60
9336580
J Clin Invest. 2007 Dec;117(12):3730-41
18037988
Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16507-12
15545607
Science. 2003 Feb 7;299(5608):896-9
12574632
Circ Res. 2007 Mar 16;100(5):599-601
17363704
Arch Biochem Biophys. 1995 Jan 10;316(1):70-6
7840680
Cardiovasc Res. 2004 Nov 1;64(2):279-88
15485687
Shock. 2007 Jul;28(1):53-8
17483742
Blood. 1997 Jan 15;89(2):680-7
9002972
J Clin Invest. 1987 Aug;80(2):357-66
3038955
Am J Respir Crit Care Med. 2007 Oct 15;176(8):768-77
17600279
Circulation. 2002 Dec 3;106(23):2973-9
12460881
Antioxid Redox Signal. 2008 Feb;10(2):269-75
17999632
FASEB J. 2005 Sep;19(11):1531-3
15994412
J Neurosci. 2008 Feb 27;28(9):2015-24
18305236
Br J Haematol. 2002 Aug;118(2):619-26
12139757
Int J Biochem Cell Biol. 2009 Oct;41(10):1949-56
19446651
Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3974-8
8171022
N Engl J Med. 2005 Aug 25;353(8):782-92
16120858
J Neurosci. 2006 Jan 25;26(4):1269-74
16436614
J Appl Physiol (1985). 2008 Apr;104(4):1154-60
18218911
Nature. 1999 Jun 10;399(6736):597-601
10376602
Fundam Clin Pharmacol. 2006 Feb;20(1):51-6
16448394
JAMA. 2008 Feb 27;299(8):914-24
18314434
Circ Res. 2008 Nov 21;103(11):1232-40
18845810
J Appl Physiol (1985). 2008 Aug;105(2):581-7
18535134
Clin Exp Pharmacol Physiol. 2008 Jul;35(7):812-9
18346168
J Appl Physiol (1985). 2001 May;90(5):1900-8
11299284