SIRT1 Controls the Transcription of the Peroxisome Proliferator-activated Receptor-γ Co-activator-1α (PGC-1α) Gene in Skeletal Muscle through the PGC-1α Autoregulatory Loop and Interaction with MyoD

Peroxisome proliferator activated receptor-gamma co-activator-1 alpha (PGC-1 alpha) 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-1 alpha 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-1 alpha mRNA expression. The transcription-promoting effects of SIRT1 occurred through stimulation of PGC-1 alpha 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-1 alpha 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-1 alpha expression loop, such that overexpression of PGC-1 alpha increased PGC-1 alpha promoter activity in the presence of co-expressed MyoD and SIRT1. Chromatin immunoprecipitation showed that SIRT1 interacts with PGC-1 alpha promoter and increases PGC-1 alpha recruitment to its own promoter region. Immunoprecipitation assays further showed that SIRT1-PGC-1 alpha interactions are enhanced by MyoD. Collectively, these data indicate that SIRT1 controls PGC-1 alpha gene expression in skeletal muscle and that MyoD is a key mediator of this action. The involvement of MyoD in SIRT1-dependent PGC-1 alpha expression may help to explain the ability of SIRT1 to drive muscle-specific gene expression and metabolism. Autoregulatory control of PGC-1 alpha gene transcription seems to be a pivotal mechanism for conferring a transcription-activating response to SIRT1 in skeletal muscle.