Functional Interdependence at the Chromatin Level between the MKK6/p38 and IGF1/PI3K/AKT Pathways during Muscle Differentiation

Abstract

During muscle regeneration, the mechanism integrating environmental cues at the chromatin of muscle progenitors is unknown. We show that inflammation-activated MKK6-p38 and insulin growth factor 1 (IGF1)-induced PI3K/AKT pathways converge on the chromatin of muscle genes to target distinct components of the muscle transcriptosome. p38 alpha/beta kinases recruit the SWI/SNF chromatin-remodeling complex; AKT1 and 2 promote the association of MyoD with p300 and PCAF acetyltransferases, via direct phosphorylation of p300. Pharmacological or genetic interference with either pathway led to partial assembly of discrete chromatin-bound complexes, which reflected two reversible and distinct cellular phenotypes. Remarkably, PI3K/AKT blockade was permissive for chromatin recruitment of MEF2-SWI/SNF complex, whose remodeling activity was compromised in the absence of MyoD and acetyltransferases. The functional interdependence between p38 and IGF1/PI3K/AKT pathways was further established by the evidence that blockade of AKT chromatin targets was sufficient to prevent the activation of the myogenic program triggered by deliberate activation of p38 signaling.

PI3K/AKT signaling determines a dynamic switch between distinct KSRP functions favoring skeletal myogenesis

“…In order to assess the contribution of the PI3K/AKT signaling pathway to myomiR induction during differentiation of C2C12 myoblasts, we continuously exposed cells to PI3K inhibitor LY294002 (LY) throughout the transition from myoblasts to myotubes induced by differentiation medium (DM). LY was able to impair DMinduced expression of myogenic differentiation markers (Supplementary Figure S1a, and Serra et al 31 ) and to strongly inhibit the expression of miR-1a, miR-133b and miR-206 (members of the myomiR family 10,11 ) induced by DM (Figure 1a). Importantly, the comparative analysis of primary and mature miRNAs revealed that LY specifically impairs myomiR maturation (Figures 1a and b).…”

“…AKT kinases are the major downsteam effectors of PI3K. 32 As the relative contribution of the two AKT isoforms expressed in C2C12 cells (Akt1 and Akt2) to differentiation is still debated, 33 we downregulated either isoform before exposure to DM (Supplementary Figure S1b) and obtained inhibition of the expression of myogenic differentiation markers (Supplementary Figure S1c, and Serra et al 31 ). Silencing experiments demonstrated that both Akt1 and Akt2 are required for DM-induced maturation of miR-1a, miR-133b and miR-206 (compare the expression of mature and primary miRNA in Figures 1c and d).…”

Prion and TNFα: TAC(E)it agreement between the prion protein and cell signaling

“…[17][18][19][20] Finally, P-p38 induces p21, an inhibitor of cyclin-dependent kinases, promoting cell cycle arrest and terminal differentiation of muscle precursors. 18,21 Interestingly, we found that the Akt kinase, which works synergistically with p38 in the SWI/SNF-mediated chromatin remodeling, 20,22 was also downregulated in regenerating PrP-KO muscles. That the absence of PrP C delayed withdrawal of muscle precursors from the cell cycle and, hence, retarded their differentiation, was further confirmed by the prolonged remarkable capacity to recover from injury and express substantial PrP C amounts.…”

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

“…8 In undifferentiated muscle cells, EZH2-mediated trimethylation of H3K27 contributes to maintaining the chromatin of muscle genes in a conformation repressive for transcription, supporting the self-renewal and proliferation of progenitor cells. [9][10][11][12][13] At the onset of differentiation, downregulation of EZH2 allows a chromatin conformation permissive for transcription of differentiation genes. [11][12][13] These data highlight the importance of EZH2 in controlling the balance between proliferation and differentiation of myogenic progenitors.…”