PC4/Tis7/IFRD1 Stimulates Skeletal Muscle Regeneration and Is Involved in Myoblast Differentiation as a Regulator of MyoD and NF-κB

Abstract

In skeletal muscle cells, the PC4 (Tis7/Ifrd1) protein is known to function as a coactivator of MyoD by promoting the transcriptional activity of myocyte enhancer factor 2C (MEF2C). In this study, we show that up-regulation of PC4 in vivo in adult muscle significantly potentiates injury-induced regeneration by enhancing myogenesis. Conversely, we observe that PC4 silencing in myoblasts causes delayed exit from the cell cycle, accompanied by delayed differentiation, and we show that such an effect is MyoD-dependent. We provide evidence revealing a novel mechanism underlying the promyogenic actions of PC4, by which PC4 functions as a negative regulator of NF-κB, known to inhibit MyoD expression post-transcriptionally. In fact, up-regulation of PC4 in primary myoblasts induces the deacetylation, and hence the inactivation and nuclear export of NF-κB p65, in concomitance with induction of MyoD expression. On the contrary, PC4 silencing in myoblasts induces the acetylation and nuclear import of p65, in parallel with a decrease of MyoD levels. We also observe that PC4 potentiates the inhibition of NF-κB transcriptional activity mediated by histone deacetylases and that PC4 is able to form trimolecular complexes with p65 and HDAC3. This suggests that PC4 stimulates deacetylation of p65 by favoring the recruitment of HDAC3 to p65. As a whole, these results indicate that PC4 plays a role in muscle differentiation by controlling the MyoD pathway through multiple mechanisms, and as such, it positively regulates regenerative myogenesis.

Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

“…NF-B is a positive regulator of osteoclastogenesis and a negative regulator of osteoblastogenesis (34,35). In addition, previous studies have demonstrated that Ifrd1 decreases and increases the activity of NF-B-dependent transcription in myoblasts and neutrophils, respectively (3,24). This suggests that depending on the cellular lineages, Ifrd1 may both negatively and positively regulate NF-B signaling.…”

“…5F). Ifrd1 modifies the acetylation status of p65 by HDACs (24). The physical interaction between HDAC1 and p65 was dramatically decreased in Ifrd1 Ϫ/Ϫ BMMs (Fig.…”

miR-203b: a novel regulator of MyoD expression in tilapia skeletal muscle

“…p300/CBP, PCAF acetyltransferases and histone deacetylases (HDACs) can be recruited onto the MyoD promoter and regulate MyoD gene expression at transcriptional level. In addition, IFRD1 can repress the transcriptional activity of NF-κB, and indirectly inhibit MyoD expression; β-catenin interacts directly with MyoD, and enhances both its binding to E box elements and its transcriptional activity; and miR-203b can regulate muscle development by direct targeting of MyoD (Francetic et al, 2012;Kim et al, 2008;Micheli et al, 2011). Thus, cells have numerous mechanisms to quantitatively regulate the dosage of MyoD expression.…”

“…Of these, MyoD is thought to be the key transcription factor that initiates the cascade of regulatory events during muscle development. MyoD can be regulated at the transcriptional level through the recruitment of both chromatin remodeling complexes and p300/CBP and PCAF acetyltransferases onto the MyoD promoter, whereas histone deacetylase (HDAC) recruitment inhibits MyoD expression (Aguiar et al, 2008;Francetic et al, 2012;Lassar, 2012); the PC4 (Tis7/Ifrd1) protein can cooperate with MyoD to induce the transcriptional activity of myocyte enhancer factor 2C (MEF2C), and repress the transcriptional activity of NF-κB to inhibit MyoD mRNA accumulation (Micheli et al, 2011). In addition, β-catenin interacts with MyoD and regulates its transcription activity (Kim et al, 2008).…”

Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal

“…phase partly through its synergistic interactions with retinoblastoma (21)(22)(23)(24)(25). In the G 1 phase retinoblastoma is hyperphosphorylated by the cyclin D⅐CDK4/CDK6 complex, causing the release and activation of the E2F⅐DP transcription factor complex, which in turn activates expression of the genes required for S-phase progression (26).…”