title: FoxO transcription factors promote autophagy in cardiomyocytes.
abstract: In the heart, autophagy is required for normal cardiac function and also has been implicated in cardiovascular disease. FoxO transcription factors promote autophagy in skeletal muscle and have additional roles in regulation of cell size, proliferation, and metabolism. Here we investigate the role of FoxO transcription factors in regulating autophagy and cell size in cardiomyocytes. In cultured rat neonatal cardiomyocytes, glucose deprivation leads to decreased cell size and induction of autophagy pathway genes LC3, Gabarapl1, and Atg12. Likewise, overexpression of either FoxO1 or FoxO3 reduces cardiomyocyte cell size and induces expression of autophagy pathway genes. Moreover, inhibition of FoxO activity by dominant negative FoxO1 (Delta256) blocks cardiomyocyte cell size reduction upon starvation, suggesting the necessity of FoxO function in cardiomyocyte cell size regulation. Under starvation conditions, endogenous FoxO1 and FoxO3 are localized to the nucleus and bind to promoter sequences of Gabarapl1 and Atg12. In vivo studies show that cellular stress, such as starvation or ischemia/reperfusion in mice, results in induction of autophagy in the heart with concomitant dephosphorylation of FoxO, consistent with increased activity of nuclear FoxO transcription factors. Together these results provide evidence for an important role for FoxO1 and FoxO3 in regulating autophagy and cell size in cardiomyocytes.
authors.affiliation: Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio 45229.
authors.forename: Arunima
authors.initials: A
authors.lastname: Sengupta
authors.affiliation: Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio 45229.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Division of Molecular Cardiovascular Biology, Cincinnati Children's Medical Center, Cincinnati, Ohio 45229. Electronic address: katherine.yutzey@cchmc.org.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Yutzey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000502:physiology*; D000071192:Autophagy-Related Protein 12; D000071190:Autophagy-Related Protein 8 Family; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013217:Starvation; D000071161:Forkhead Box Protein O1
chemical_list: D000071192:Autophagy-Related Protein 12; D000071190:Autophagy-Related Protein 8 Family; D002352:Carrier Proteins; D003470:Culture Media; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C491971:Atg12 protein, mouse; C499515:FOXO3 protein, rat; C407740:Gabarapl2 protein, mouse; C480860:Map1lc3b protein, mouse; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):11946-51
references.pmid: 16882732
references.citation: J Card Fail. 2006 Jun;12(5):381-91
references.pmid: 16762802
references.citation: Science. 2004 Mar 26;303(5666):2011-5
references.pmid: 14976264
references.citation: Nucleic Acids Res. 1993 Jan 25;21(2):223-31
references.pmid: 8441630
references.citation: J Mol Cell Cardiol. 2006 Jun;40(6):846-52
references.pmid: 16697404
references.citation: Circulation. 2006 Sep 19;114(12):1269-76
references.pmid: 16952980
references.citation: Cell. 2004 Apr 30;117(3):399-412
references.pmid: 15109499
references.citation: Mol Biol Cell. 2004 Mar;15(3):1101-11
references.pmid: 14699058
references.citation: Circulation. 2006 Sep 12;114(11):1159-68
references.pmid: 16952979
references.citation: Circulation. 1998 Aug 18;98(7):656-62
references.pmid: 9715858
references.citation: J Biol Chem. 2006 Oct 6;281(40):29776-87
references.pmid: 16882669
references.citation: Circ Res. 2003 Apr 18;92(7):715-24
references.pmid: 12649263
references.citation: J Clin Invest. 2004 Oct;114(8):1058-71
references.pmid: 15489953
references.citation: Nat Med. 2007 May;13(5):619-24
references.pmid: 17450150
references.citation: Nature. 2004 Dec 23;432(7020):1032-6
references.pmid: 15525940
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2975-80
references.pmid: 14978268
references.citation: Circ Res. 2007 Mar 30;100(6):914-22
references.pmid: 17332429
references.citation: Cell. 2008 Jan 11;132(1):27-42
references.pmid: 18191218
references.citation: Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1599-607
references.pmid: 18708438
references.citation: Circ Res. 1974 Jul;35(1):127-35
references.pmid: 4276275
references.citation: Circulation. 2004 Apr 6;109(13):1580-9
references.pmid: 15066961
references.citation: Cell. 1999 Mar 19;96(6):857-68
references.pmid: 10102273
references.citation: Circ Res. 2008 Aug 15;103(4):343-51
references.pmid: 18703786
references.citation: Circulation. 2000 Feb 15;101(6):660-7
references.pmid: 10673259
references.citation: J Mol Cell Cardiol. 2008 Apr;44(4):654-61
references.pmid: 18353358
references.citation: J Clin Invest. 2001 Nov;108(9):1359-67
references.pmid: 11696581
references.citation: Autophagy. 2008 May;4(4):409-15
references.pmid: 18227645
references.citation: Nature. 2009 Apr 23;458(7241):1056-60
references.pmid: 19262508
references.citation: Nat Rev Mol Cell Biol. 2006 Aug;7(8):589-600
references.pmid: 16936699
references.citation: J Cell Sci. 2007 Aug 1;120(Pt 15):2479-87
references.pmid: 17646672
references.citation: Circ Res. 2009 Jan 30;104(2):150-8
references.pmid: 19179668
references.citation: Autophagy. 2008 May;4(4):416-21
references.pmid: 18253087
references.citation: J Am Coll Cardiol. 2004 Jun 16;43(12):2191-9
references.pmid: 15193679
references.citation: Oncogene. 2005 Nov 14;24(50):7410-25
references.pmid: 16288288
references.citation: Circulation. 2001 Jul 17;104(3):330-5
references.pmid: 11457753
references.citation: Science. 2004 Nov 5;306(5698):990-5
references.pmid: 15528435
references.citation: Dev Cell. 2003 Jan;4(1):119-29
references.pmid: 12530968
references.citation: Trends Endocrinol Metab. 2005 May-Jun;16(4):183-9
references.pmid: 15860415
references.citation: J Biol Chem. 2007 Oct 12;282(41):30107-19
references.pmid: 17711846
references.citation: Cell Death Differ. 2007 Jan;14(1):146-57
references.pmid: 16645637
references.citation: J Cell Biol. 2003 Aug 18;162(4):535-41
references.pmid: 12925703
references.citation: J Clin Invest. 2007 Jul;117(7):1782-93
references.pmid: 17607355
references.citation: Dev Biol. 2007 Feb 15;302(2):376-88
references.pmid: 17064679
references.citation: Cell Metab. 2007 Dec;6(6):472-83
references.pmid: 18054316
references.citation: Cell Death Differ. 2009 Jan;16(1):31-8
references.pmid: 19008922
references.citation: FEBS Lett. 2008 Jul 9;582(16):2417-23
references.pmid: 18544345
references.citation: Development. 2008 Aug;135(14):2347-60
references.pmid: 18567846
references.citation: Autophagy. 2008 May;4(4):507-9
references.pmid: 18259117
references.citation: Circulation. 2006 May 16;113(19):e759-61
references.pmid: 16702477
references.citation: Cell Metab. 2007 Dec;6(6):458-71
references.pmid: 18054315
references.citation: Science. 2004 Dec 17;306(5704):2105-8
references.pmid: 15604409
references.citation: J Biol Chem. 2004 Jan 9;279(2):1513-25
references.pmid: 14551207
references.citation: J Biol Chem. 2004 Apr 9;279(15):15524-30
references.pmid: 14749328
references.citation: J Biol Chem. 2000 May 5;275(18):13571-9
references.pmid: 10788473
references.citation: Circ Res. 2008 Mar 28;102(6):686-94
references.pmid: 18218983
references.citation: Nature. 2000 Aug 24;406(6798):902-6
references.pmid: 10972293
references.citation: J Biol Chem. 2005 Sep 23;280(38):32602-8
references.pmid: 16043490
references.citation: Br Heart J. 1994 Mar;71(3):287-92
references.pmid: 8142200
references.citation: J Biol Chem. 2005 May 27;280(21):20814-23
references.pmid: 15781459
references.citation: J Mol Cell Cardiol. 1996 Aug;28(8):1737-46
references.pmid: 8877783
references.citation: Nat Rev Mol Cell Biol. 2001 Mar;2(3):211-6
references.pmid: 11265251
references.citation: J Clin Invest. 2005 Oct;115(10):2679-88
references.pmid: 16200202