title: Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy.
abstract: Cachexia is characterized by inexorable muscle wasting that significantly affects patient prognosis and increases mortality. Therefore, understanding the molecular basis of this muscle wasting is of significant importance. Recent work showed that components of the forkhead box O (FoxO) pathway are increased in skeletal muscle during cachexia. In the current study, we tested the physiological significance of FoxO activation in the progression of muscle atrophy associated with cachexia. FoxO-DNA binding dependent transcription was blocked in the muscles of mice through injection of a dominant negative (DN) FoxO expression plasmid prior to inoculation with Lewis lung carcinoma cells or the induction of sepsis. Expression of DN FoxO inhibited the increased mRNA levels of atrogin-1, MuRF1, cathepsin L, and/or Bnip3 and inhibited muscle fiber atrophy during cancer cachexia and sepsis. Interestingly, during control conditions, expression of DN FoxO decreased myostatin expression, increased MyoD expression and satellite cell proliferation, and induced fiber hypertrophy, which required de novo protein synthesis. Collectively, these data show that FoxO-DNA binding-dependent transcription is necessary for normal muscle fiber atrophy during cancer cachexia and sepsis, and further suggest that basal levels of FoxO play an important role during normal conditions to depress satellite cell activation and limit muscle growth.
authors.affiliation: Department of Physical Therapy, 101 S. Newell Dr., University of Florida, Gainesville, FL 32611, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Reed
authors.forename: Pooja B
authors.initials: PB
authors.lastname: Sandesara
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Senf
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Judge
mesh_terms: D000818:Animals; D002100:Cachexia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006984:Hypertrophy; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D055435:Myostatin / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; C525912:Mstn protein, mouse; D009124:Muscle Proteins; D055435:Myostatin; D011500:Protein Synthesis Inhibitors; D000070584:Tripartite Motif Proteins; D003513:Cycloheximide; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases
references.citation: Am J Physiol Endocrinol Metab. 2011 Jun;300(6):E993-E1001
references.pmid: 21406613
references.citation: J Clin Invest. 2007 Sep;117(9):2477-85
references.pmid: 17717603
references.citation: Am J Physiol Cell Physiol. 2009 Jun;296(6):C1248-57
references.pmid: 19357234
references.citation: Contrib Nephrol. 2010;167:14-24
references.pmid: 20519895
references.citation: PLoS Biol. 2009 Feb 10;7(2):e38
references.pmid: 19209957
references.citation: J Cell Biol. 2004 Aug 2;166(3):347-57
references.pmid: 15277541
references.citation: Physiol Rev. 2004 Jan;84(1):209-38
references.pmid: 14715915
references.citation: Biochem Biophys Res Commun. 1996 Apr 25;221(3):653-5
references.pmid: 8630016
references.citation: J Am Soc Nephrol. 2004 Jun;15(6):1537-45
references.pmid: 15153564
references.citation: Nature. 1997 May 1;387(6628):83-90
references.pmid: 9139826
references.citation: Endocrinology. 2008 Mar;149(3):1407-14
references.pmid: 18079193
references.citation: FEBS Lett. 2010 Jun 3;584(11):2403-8
references.pmid: 20412806
references.citation: J Trauma. 1982 Apr;22(4):263-73
references.pmid: 6281451
references.citation: Surgery. 1990 Aug;108(2):460-6
references.pmid: 2382237
references.citation: J Clin Invest. 2004 Aug;114(3):370-8
references.pmid: 15286803
references.citation: Am J Physiol Endocrinol Metab. 2007 Feb;292(2):E501-12
references.pmid: 17003238
references.citation: Am J Physiol Cell Physiol. 2010 Jan;298(1):C38-45
references.pmid: 19864323
references.citation: Am J Clin Nutr. 1989 Sep;50(3):444-7
references.pmid: 2773823
references.citation: Biochem J. 2010 Mar 15;427(1):171-8
references.pmid: 20088826
references.citation: J Biol Chem. 2005 Apr 15;280(15):15013-9
references.pmid: 15728188
references.citation: Annu Rev Cell Dev Biol. 2004;20:61-86
references.pmid: 15473835
references.citation: FASEB J. 2004 Jan;18(1):39-51
references.pmid: 14718385
references.citation: Muscle Nerve. 2005 Mar;31(3):339-48
references.pmid: 15751123
references.citation: PLoS One. 2009 Sep 14;4(9):e6945
references.pmid: 19759896
references.citation: Dev Cell. 2010 Apr 20;18(4):592-604
references.pmid: 20412774
references.citation: Am J Physiol Regul Integr Comp Physiol. 2006 Jun;290(6):R1589-97
references.pmid: 16455766
references.citation: Genes Dev. 2004 Aug 15;18(16):1926-45
references.pmid: 15314020
references.citation: Arch Intern Med. 2000 Mar 27;160(6):861-8
references.pmid: 10737287
references.citation: Cell. 2000 Sep 15;102(6):777-86
references.pmid: 11030621
references.citation: J Biol Chem. 2004 Sep 24;279(39):41114-23
references.pmid: 15272020
references.citation: Int J Clin Exp Med. 2008;1(1):50-63
references.pmid: 19079687
references.citation: Am J Physiol Regul Integr Comp Physiol. 2010 Aug;299(2):R509-20
references.pmid: 20538901
references.citation: Cancer Gene Ther. 2007 Dec;14(12):945-52
references.pmid: 17885675
references.citation: J Physiol. 2003 Aug 15;551(Pt 1):33-48
references.pmid: 12844509
references.citation: Methods Mol Biol. 2008;433:115-25
references.pmid: 18679620
references.citation: Clin Nutr. 2008 Dec;27(6):793-9
references.pmid: 18718696
references.citation: Int J Biochem Cell Biol. 2003 May;35(5):698-705
references.pmid: 12672461
references.citation: FASEB J. 2008 Nov;22(11):3836-45
references.pmid: 18644837
references.citation: J Cell Biol. 2002 Feb 4;156(3):531-42
references.pmid: 11815629
references.citation: Am J Med. 1980 Oct;69(4):491-7
references.pmid: 7424938
references.citation: Cell Metab. 2007 Dec;6(6):472-83
references.pmid: 18054316
references.citation: Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E785-97
references.pmid: 18612045
references.citation: Clin Biochem. 2007 Dec;40(18):1353-60
references.pmid: 17931612
references.citation: J Mol Med (Berl). 2007 Jun;85(6):647-54
references.pmid: 17333095
references.citation: Lancet. 1997 Apr 12;349(9058):1050-3
references.pmid: 9107242
references.citation: Cancer Cell. 2005 Nov;8(5):421-32
references.pmid: 16286249
references.citation: Pflugers Arch. 2008 Jun;456(3):587-600
references.pmid: 18193272
references.citation: Dev Biol. 1997 Nov 15;191(2):270-83
references.pmid: 9398440
references.citation: Oncol Rep. 2007 Dec;18(6):1521-7
references.pmid: 17982639
references.citation: Mediators Inflamm. 2008;2008:317851
references.pmid: 18389075
references.citation: J Am Soc Nephrol. 2004 Dec;15(12):3134-43
references.pmid: 15579517
references.citation: Endocrinology. 2007 Jul;148(7):3140-7
references.pmid: 17395701
references.citation: Cell Metab. 2007 Dec;6(6):458-71
references.pmid: 18054315
references.citation: Int J Biochem Cell Biol. 2010 May;42(5):701-11
references.pmid: 20079455
references.citation: Cell. 2004 Apr 30;117(3):399-412
references.pmid: 15109499
references.citation: Biochem Biophys Res Commun. 2001 Mar;281(5):1331-6
references.pmid: 11243882
references.citation: Eur J Cancer. 1991;27(2):182-7
references.pmid: 1827286
references.citation: Metabolism. 1989 Jul;38(7):634-40
references.pmid: 2661965
references.citation: Science. 2001 Nov 23;294(5547):1704-8
references.pmid: 11679633
references.citation: Int J Cancer. 2010 Feb 1;126(3):756-63
references.pmid: 19634137
references.citation: Am J Pathol. 2007 Feb;170(2):599-608
references.pmid: 17255328
references.citation: Cancer. 1979 May;43(5 Suppl):2065-9
references.pmid: 445386
references.citation: Int J Cancer. 1999 Mar 1;80(5):756-63
references.pmid: 10048979
references.citation: Circ Res. 2005 Sep 2;97(5):418-26
references.pmid: 16051886
references.citation: J Clin Invest. 1992 May;89(5):1681-4
references.pmid: 1569207
references.citation: Biochem Biophys Res Commun. 2011 Feb 18;405(3):491-6
references.pmid: 21256828
references.citation: Dev Biol. 1994 Aug;164(2):588-603
references.pmid: 7913900
references.citation: J Physiol. 2008 Nov 15;586(22):5589-600
references.pmid: 18818241
references.citation: Int J Biochem Cell Biol. 2005 Oct;37(10):2156-68
references.pmid: 16125115
references.citation: Am J Clin Nutr. 2006 Jun;83(6):1345-50
references.pmid: 16762946
references.citation: Am J Physiol Cell Physiol. 2007 Jan;292(1):C188-99
references.pmid: 16885393
references.citation: Am J Physiol Endocrinol Metab. 2010 Oct;299(4):E533-43
references.pmid: 20647557
references.citation: J Clin Invest. 1993 Dec;92(6):2783-9
references.pmid: 8254032
references.citation: Br J Cancer. 2004 May 17;90(10):1905-11
references.pmid: 15138470
references.citation: Am J Physiol Cell Physiol. 2008 Oct;295(4):C986-93
references.pmid: 18701653
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Feb;282(2):R439-44
references.pmid: 11792653
references.citation: Eur J Cancer. 2008 May;44(8):1124-32
references.pmid: 18375115
references.citation: Mol Ther. 2006 Apr;13(4):795-803
references.pmid: 16309967