SIRT1 controls the transcription of the peroxisome proliferator-activated receptor-gamma Co-activator-1alpha (PGC-1alpha) gene in skeletal muscle through the PGC-1alpha autoregulatory loop and interaction with MyoD.
Peroxisome proliferator activated receptor-gamma co-activator-1alpha (PGC-1alpha) is a transcriptional co-activator that coordinately regulates the expression of distinct sets of metabolism-related genes in different tissues. Here we show that PGC-1alpha expression is reduced in skeletal muscles from mice lacking the sirtuin family deacetylase SIRT1. Conversely, SIRT1 activation or overexpression in differentiated C2C12 myotubes increased PGC-1alpha mRNA expression. The transcription-promoting effects of SIRT1 occurred through stimulation of PGC-1alpha promoter activity and were enhanced by co-transfection of myogenic factors, such as myocyte enhancer factor 2 (MEF2) and, especially, myogenic determining factor (MyoD). SIRT1 bound to the proximal promoter region of the PGC-1alpha gene, an interaction potentiated by MEF2C or MyoD, which also interact with this region. In the presence of MyoD, SIRT1 promoted a positive autoregulatory PGC-1alpha expression loop, such that overexpression of PGC-1alpha increased PGC-1alpha promoter activity in the presence of co-expressed MyoD and SIRT1. Chromatin immunoprecipitation showed that SIRT1 interacts with PGC-1alpha promoter and increases PGC-1alpha recruitment to its own promoter region. Immunoprecipitation assays further showed that SIRT1-PGC-1alpha interactions are enhanced by MyoD. Collectively, these data indicate that SIRT1 controls PGC-1alpha gene expression in skeletal muscle and that MyoD is a key mediator of this action. The involvement of MyoD in SIRT1-dependent PGC-1alpha expression may help to explain the ability of SIRT1 to drive muscle-specific gene expression and metabolism. Autoregulatory control of PGC-1alpha gene transcription seems to be a pivotal mechanism for conferring a transcription-activating response to SIRT1 in skeletal muscle.
Amat
Ramon
R
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Planavila
Anna
A
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Chen
Shen Liang
SL
Department of Life Sciences, National Central University, Jhongli 32054, Taiwan.
Iglesias
Roser
R
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Giralt
Marta
M
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
Villarroya
Francesc
F
Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB) and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona 08028, Spain.
D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism*; D017570:MyoD Protein / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins