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

Abstract

Peroxisome proliferator activated receptor-␥ co-activator-1␣ (PGC-1␣) 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␣ 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␣ mRNA expression. The transcription-promoting effects of SIRT1 occurred through stimulation of PGC-1␣ 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␣ 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␣ expression loop, such that overexpression of PGC-1␣ increased PGC-1␣ promoter activity in the presence of co-expressed MyoD and SIRT1. Chromatin immunoprecipitation showed that SIRT1 interacts with PGC-1␣ promoter and increases PGC-1␣ recruitment to its own promoter region. Immunoprecipitation assays further showed that SIRT1-PGC-1␣ interactions are enhanced by MyoD. Collectively, these data indicate that SIRT1 controls PGC-1␣ gene expression in skeletal muscle and that MyoD is a key mediator of this action. The involvement of MyoD in SIRT1-dependent PGC-1␣ expression may help to explain the ability of SIRT1 to drive musclespecific gene expression and metabolism. Autoregulatory control of PGC-1␣ gene transcription seems to be a pivotal mechanism for conferring a transcription-activating response to SIRT1 in skeletal muscle.Peroxisome proliferator activated receptor-␥ co-activator-1␣ (PGC-1␣) 2 is a transcriptional co-activator that is recognized as a master controller of the expression of genes involved in metabolic regulation. PGC-1␣ exerts differential effects on metabolism in different tissues. In brown adipose tissue, PGC-1␣ increases the expression of uncoupling protein 1 and genes involved in mitochondrial oxidative pathways. In the liver, PGC-1␣ induces the expression of genes involved in gluconeogenesis and the metabolic response to starvation. In skeletal muscle, PGC-1␣ expression is rapidly induced by exercise in vivo (1), a response considered to be a mechanism for modulating metabolic flux in response to decreased ATP levels (2). Chronic exercise also increases PGC-1␣ expression in association with fiber-type switching toward the more oxidative and high endurance type IIa and type I fibers. The fiber-type switch promoted by PGC-1␣ is characterized by increased mitochondrial density and function, increased oxidative metabolism, increased expression of myofibrillar proteins characteristic of type I and type IIa muscle fibers and a switch in substrate fuel usage (3). Furthermore, greater levels of PGC-1␣ are found in oxidative fibers compared with glycolytic fibers, even in a rested state (3). Mo...

Sirtuin 1 (SIRT1) Deacetylase Activity Is Not Required for Mitochondrial Biogenesis or Peroxisome Proliferator-activated Receptor-γ Coactivator-1α (PGC-1α) Deacetylation following Endurance Exercise

“…In addition to post-translational modification of PGC-1␣, SIRT1 has also been reported to regulate PGC-1␣ transcriptional activity via interaction with myogenic regulatory factors at an autoregulatory region in the PGC-1␣ promoter (34). At 3 h after AEX, we observed a marked increase in PGC-1␣ gene expression in mKO compared with WT mice.…”

“…Therefore, altered activation of these pathways does not appear to explain the ability of mKO to adapt to VWR and AEX. PGC-1␣ gene transcription is well known to be induced by exercise (7,9,33), and SIRT1 has been reported to be involved in regulating PGC-1␣ promoter activity (19,20,34). However, we found that skeletal muscle PGC-1␣ expression was significantly increased 3 h after AEX in both WT and mKO mice compared with SED mice, and in fact, the increase in mKO mice 3 h after AEX was ϳ2-fold greater than that of WT mice (Fig.…”

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

“…SIRT1 has been reported to deacetylate the lysine residues of a number of nuclear proteins, such as p53 (Yuan et al., 2011), NF‐κB (Salminen & Kaarniranta, 2009), PGC‐1a (Amat et al., 2009), CBP/p300 (Das, Lucia, Hansen & Tyler, 2009), and forkhead family proteins (Brunet et al., 2004). Several recent studies demonstrated that Sirt1 could inhibit TGF‐β signaling and ameliorate fibrosis (Huang et al., 2014; Kume et al., 2007; Zerr et al., 2014).…”

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

“…Adenoviral-mediated gene transduction. A recombinant adenovirus expressing murine Sirt1 cDNA was constructed (Ad5-CMV-Sirt1, CEBATEG, Barcelona) 37 . NCMs were infected with the Sirt1 adenoviral vector (Sirt1) or an AdCMV-GFP control vector (GFP) at 10 IFU per cell for 24 h in serum-free medium.…”