title: AMPKalpha1 deletion shortens erythrocyte life span in mice: role of oxidative stress.
abstract: AMP-activated protein kinase (AMPK) is an energy sensor essential for maintaining cellular energy homeostasis. Here, we report that AMPKalpha1 is the predominant isoform of AMPK in murine erythrocytes and mice globally deficient in AMPKalpha1 (AMPKalpha1(-/-)), but not in those lacking AMPKalpha2, and the mice had markedly enlarged spleens with dramatically increased proportions of Ter119-positive erythroid cells. Blood tests revealed significantly decreased erythrocyte and hemoglobin levels with increased reticulocyte counts and elevated plasma erythropoietin concentrations in AMPKalpha1(-/-) mice. The life span of erythrocytes from AMPKalpha1(-/-) mice was less than that in wild-type littermates, and the levels of reactive oxygen species and oxidized proteins were significantly increased in AMPKalpha1(-/-) erythrocytes. In keeping with the elevated oxidative stress, treatment of AMPKalpha1(-/-) mice with the antioxidant, tempol, resulted in decreased reticulocyte counts and improved erythrocyte survival. Furthermore, the expression of Foxo3 and reactive oxygen species scavenging enzymes was significantly decreased in erythroblasts from AMPKalpha1(-/-) mice. Collectively, these results establish an essential role for AMPKalpha1 in regulating oxidative stress and life span in erythrocytes.
authors.affiliation: Division of Endocrinology and Diabetes, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Shaobin
authors.initials: S
authors.lastname: Wang
authors.forename: George L
authors.initials: GL
authors.lastname: Dale
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004906:Erythrocyte Count; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004921:Erythropoietin / Q000097:blood / Q000378:metabolism; D005434:Flow Cytometry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010659:Phenylhydrazines / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000097:blood / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013163:Splenomegaly / Q000201:enzymology / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D013997:Time Factors; D000099156:Superoxide Dismutase 2
chemical_list: D055372:AMP-Activated Protein Kinases; D004921:Erythropoietin; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016877:Oxidants; D010659:Phenylhydrazines; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C474033:FoxO3 protein, mouse; C030299:phenylhydrazine; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse
references.citation: Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1205-16
references.pmid: 16910768
references.citation: Biochem J. 2007 Mar 1;402(2):219-27
references.pmid: 17059387
references.citation: Prostaglandins Other Lipid Mediat. 2007 Jan;82(1-4):119-27
references.pmid: 17164139
references.citation: J Appl Physiol (1985). 2000 Jun;88(6):2219-26
references.pmid: 10846039
references.citation: J Lab Clin Med. 1976 Aug;88(2):328-33
references.pmid: 956688
references.citation: Blood. 2004 Oct 15;104(8):2565-73
references.pmid: 15205258
references.citation: Blood. 2007 Jul 15;110(2):762-9
references.pmid: 17395782
references.citation: J Clin Invest. 1985 Nov;76(5):1971-7
references.pmid: 4056060
references.citation: Blood. 2006 Jan 1;107(1):341-8
references.pmid: 16141346
references.citation: FEBS Lett. 2003 Jul 3;546(1):113-20
references.pmid: 12829246
references.citation: J Clin Invest. 1980 Sep;66(3):563-73
references.pmid: 6156955
references.citation: Clin Chim Acta. 2008 Apr;390(1-2):1-11
references.pmid: 18243141
references.citation: Science. 2000 Jun 16;288(5473):2051-4
references.pmid: 10856220
references.citation: Blood. 2003 Jun 15;101(12):5033-8
references.pmid: 12586629
references.citation: Blood. 2001 Dec 1;98(12):3261-73
references.pmid: 11719363
references.citation: Blood. 2008 Nov 15;112(10):3939-48
references.pmid: 18988878
references.citation: Semin Hematol. 1979 Apr;16(2):95-114
references.pmid: 384522
references.citation: Blood. 2006 Jul 1;108(1):123-33
references.pmid: 16527892
references.citation: J Biol Chem. 2003 Sep 5;278(36):34003-10
references.pmid: 12824177
references.citation: Diabetes. 2008 Dec;57(12):3222-30
references.pmid: 18835932
references.citation: Blood. 2003 Dec 1;102(12):3938-46
references.pmid: 12907435
references.citation: J Clin Pathol. 1999 Apr;52(4):241-4
references.pmid: 10474511
references.citation: Methods Enzymol. 1994;233:346-57
references.pmid: 8015469
references.citation: J Biol Chem. 2007 Oct 12;282(41):30107-19
references.pmid: 17711846
references.citation: Free Radic Biol Med. 2005 Dec 1;39(11):1407-17
references.pmid: 16274876
references.citation: Nature. 2002 Sep 19;419(6904):316-21
references.pmid: 12239572
references.citation: Nature. 1975 Aug 21;256(5519):665-7
references.pmid: 1153002
references.citation: Blood. 1990 Sep 1;76(5):1015-20
references.pmid: 2393710
references.citation: Circ Res. 2005 Apr 29;96(8):838-46
references.pmid: 15790954
references.citation: Circ Res. 2010 Apr 2;106(6):1117-28
references.pmid: 20167927
references.citation: Toxicol Pathol. 2006;34(5):455-65
references.pmid: 17067939
references.citation: Br J Haematol. 2008 May;141(3):367-75
references.pmid: 18341630
references.citation: C R Acad Sci III. 1997 Oct;320(10):811-8
references.pmid: 9436535
references.citation: Nat Rev Immunol. 2005 Aug;5(8):606-16
references.pmid: 16056254
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Blood. 1987 Sep;70(3):791-5
references.pmid: 3304462
references.citation: Annu Rev Biochem. 1993;62:797-821
references.pmid: 8352601
references.citation: Biochem J. 2009 Jun 26;421(2):163-9
references.pmid: 19442239
references.citation: Nature. 2003 Jul 31;424(6948):561-5
references.pmid: 12891360
references.citation: FASEB J. 2009 Apr;23(4):1072-80
references.pmid: 19050047
references.citation: Cell Metab. 2005 Jan;1(1):15-25
references.pmid: 16054041
references.citation: J Clin Invest. 2007 Aug;117(8):2133-44
references.pmid: 17671650
references.citation: Nutrition. 2001 Feb;17(2):161, 163-5
references.pmid: 11240347
references.citation: J Biol Chem. 2004 Jan 9;279(2):1070-9
references.pmid: 14573616
references.citation: Curr Mol Med. 2008 Nov;8(7):609-19
references.pmid: 18991647
references.citation: Cell Stem Cell. 2007 Aug 16;1(2):140-52
references.pmid: 18371346
references.citation: J Clin Invest. 2003 Jan;111(1):91-8
references.pmid: 12511592
references.citation: Ann Hematol. 1993 Aug;67(2):81-7
references.pmid: 8347734