title: Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy.
abstract: Overexpression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), like exercise, increases mitochondrial content and inhibits muscle atrophy. To understand these actions, we tested whether PGC-1alpha or its close homolog, PGC-1beta, influences muscle protein turnover. In myotubes, overexpression of either coactivator increased protein content by decreasing overall protein degradation without altering protein synthesis rates. Elevated PGC-1alpha or PGC-1beta also prevented the acceleration of proteolysis induced by starvation or FoxO transcription factors and prevented the induction of autophagy and atrophy-specific ubiquitin ligases by a constitutively active FoxO3. In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB. However, increasing muscle PGC-1alpha levels pharmacologically by treatment of mice with 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside failed to block loss of muscle mass or induction of ubiquitin ligases upon denervation atrophy, although it prevented loss of mitochondria. This capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Brault
authors.forename: Jakob G
authors.initials: JG
authors.lastname: Jespersen
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001284:Atrophy / Q000473:pathology; D001343:Autophagy; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009132:Muscles / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology; D012265:Ribonucleotides / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D016328:NF-kappa B; D012263:Ribonucleosides; D012265:Ribonucleotides; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C031143:AICA ribonucleotide
references.citation: J Biol Chem. 1990 May 25;265(15):8550-7
references.pmid: 2187867
references.citation: FASEB J. 2004 Jan;18(1):39-51
references.pmid: 14718385
references.citation: J Clin Invest. 2007 Dec;117(12):3940-51
references.pmid: 17992259
references.citation: J Clin Invest. 2007 Apr;117(4):889-901
references.pmid: 17380205
references.citation: Curr Opin Clin Nutr Metab Care. 2003 Jan;6(1):87-93
references.pmid: 12496685
references.citation: Am J Physiol Endocrinol Metab. 2007 Jun;292(6):E1555-67
references.pmid: 17264220
references.citation: Am J Physiol Endocrinol Metab. 2005 Dec;289(6):E960-8
references.pmid: 16014350
references.citation: J Morphol. 1994 Aug;221(2):177-90
references.pmid: 7932768
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14440-5
references.pmid: 11717410
references.citation: Cell Metab. 2005 Jun;1(6):361-70
references.pmid: 16054085
references.citation: FASEB J. 2002 Dec;16(14):1879-86
references.pmid: 12468452
references.citation: Biochem J. 2003 Jul 1;373(Pt 1):155-65
references.pmid: 12678921
references.citation: Circ Res. 2007 Feb 16;100(3):328-41
references.pmid: 17307971
references.citation: J Biol Chem. 2009 Feb 20;284(8):5148-57
references.pmid: 19103600
references.citation: Cell. 2004 Oct 15;119(2):285-98
references.pmid: 15479644
references.citation: FASEB J. 2000 Jan;14(1):103-10
references.pmid: 10627285
references.citation: J Histochem Cytochem. 1980 May;28(5):408-12
references.pmid: 6966645
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16260-5
references.pmid: 17053067
references.citation: Cell Death Differ. 2009 Jul;16(7):939-46
references.pmid: 19229244
references.citation: J Appl Physiol (1985). 2003 Sep;95(3):960-8
references.pmid: 12777406
references.citation: Cell. 1999 Jul 9;98(1):115-24
references.pmid: 10412986
references.citation: Biochem Biophys Res Commun. 2000 Aug 2;274(2):350-4
references.pmid: 10913342
references.citation: J Appl Physiol (1985). 2000 Jun;88(6):2219-26
references.pmid: 10846039
references.citation: Mol Cell. 2004 Nov 5;16(3):399-411
references.pmid: 15525513
references.citation: Nat Med. 2008 Sep;14(9):959-65
references.pmid: 18690243
references.citation: J Biol Chem. 2003 Jul 18;278(29):26597-603
references.pmid: 12734177
references.citation: J Clin Invest. 2006 Nov;116(11):2945-54
references.pmid: 17080195
references.citation: Biochim Biophys Acta. 1998 Jun 5;1381(1):113-22
references.pmid: 9659378
references.citation: Proc Natl Acad Sci U S A. 2007 May 8;104(19):7933-8
references.pmid: 17470778
references.citation: Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E331-9
references.pmid: 16954334
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20405-10
references.pmid: 19918075
references.citation: Am J Physiol. 1991 Apr;260(4 Pt 1):C841-50
references.pmid: 1850197
references.citation: Nature. 2002 Aug 15;418(6899):797-801
references.pmid: 12181572
references.citation: Cell. 2008 Aug 8;134(3):405-15
references.pmid: 18674809
references.citation: Mol Cell. 2004 May 7;14(3):395-403
references.pmid: 15125842
references.citation: FASEB J. 2007 Jan;21(1):140-55
references.pmid: 17116744
references.citation: FASEB J. 2009 Feb;23(2):362-70
references.pmid: 18827022
references.citation: Cell Mol Life Sci. 2008 Nov;65(23):3737-55
references.pmid: 18810325
references.citation: Diabetes. 2007 Aug;56(8):2078-84
references.pmid: 17513706
references.citation: Nature. 2003 May 29;423(6939):550-5
references.pmid: 12754525
references.citation: J Clin Invest. 1997 Jul 1;100(1):197-203
references.pmid: 9202072
references.citation: J Biol Chem. 2007 Oct 12;282(41):30014-21
references.pmid: 17702743
references.citation: Cell Metab. 2007 Dec;6(6):472-83
references.pmid: 18054316
references.citation: J Appl Physiol (1985). 2007 Mar;102(3):1143-51
references.pmid: 17122379
references.citation: Methods Enzymol. 1976;44:11-9
references.pmid: 1021677
references.citation: FASEB J. 2009 Oct;23(10):3415-23
references.pmid: 19528257
references.citation: J Appl Physiol (1985). 2008 Jul;105(1):114-20
references.pmid: 18450984
references.citation: Physiol Rev. 2008 Apr;88(2):611-38
references.pmid: 18391175
references.citation: N Engl J Med. 2008 Oct 23;359(17):1842-4
references.pmid: 18946072
references.citation: J Appl Physiol (1985). 1999 Nov;87(5):1990-5
references.pmid: 10562646
references.citation: Cell Metab. 2007 Dec;6(6):458-71
references.pmid: 18054315
references.citation: Biosci Biotechnol Biochem. 2007 Jul;71(7):1650-6
references.pmid: 17617726
references.citation: Cell. 2004 Apr 30;117(3):399-412
references.pmid: 15109499
references.citation: Curr Opin Genet Dev. 2008 Feb;18(1):1-2
references.pmid: 18440220
references.citation: Cell Metab. 2007 Jan;5(1):35-46
references.pmid: 17189205
references.citation: PLoS One. 2008;3(10):e3614
references.pmid: 18974883
references.citation: Am J Physiol Cell Physiol. 2003 Jun;284(6):C1669-77
references.pmid: 12734114
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Feb;292(2):R971-6
references.pmid: 17008454
references.citation: Science. 2001 Nov 23;294(5547):1704-8
references.pmid: 11679633
references.citation: J Biol Chem. 2005 May 20;280(20):19587-93
references.pmid: 15767263
references.citation: J Cell Biol. 2009 Jun 15;185(6):1083-95
references.pmid: 19506036
references.citation: Cell. 2006 Oct 20;127(2):397-408
references.pmid: 17055439
references.citation: J Cell Biol. 2008 Aug 25;182(4):663-73
references.pmid: 18725537
references.citation: J Appl Physiol (1985). 2007 Nov;103(5):1644-54
references.pmid: 17872405
references.citation: J Biol Chem. 1969 Jun 25;244(12):3223-9
references.pmid: 5792658
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12017-22
references.pmid: 17609368
references.citation: Cell Metab. 2008 Aug;8(2):96-8
references.pmid: 18680710
references.citation: Am J Physiol Endocrinol Metab. 2004 Oct;287(4):E591-601
references.pmid: 15100091
references.citation: J Biol Chem. 2009 May 22;284(21):14476-84
references.pmid: 19324885
references.citation: J Nutr. 1999 Jan;129(1S Suppl):227S-237S
references.pmid: 9915905
references.citation: Am J Physiol Cell Physiol. 2006 Sep;291(3):C518-28
references.pmid: 16611740