Transcription factors and kinases regulating the different stages of myogenesis. A graphical representation of myogenesis is shown. Embryonic precursors or quiescent satellite cells become activated to form proliferating myoblasts, which differentiate into myocytes that fuse to form a multinucleated myotube. The upper portion of the figure shows the myogenic transcription factors required for this process and the stages for which they are required. The lower portion shows the myogenic protein kinases and the stages that they regulate.

Regulation of the early myogenic transcriptional program by the kinome. The figure shows the mechanisms by which the kinases described in the text coordinate embryonic precursor activation, myoblast proliferation and the prevention of premature myoblast differentiation. Wnt1 and Wnt7a stimulation of precursor cells activates protein kinase A (PKA), which, through the phosphorylation of CREB, induces the expression of the myogenic transcription factors Myf5, MyoD and Pax3, resulting in the myogenic commitment of embryonic precursors. PKA then prevents the premature differentiation of proliferating myoblasts by phosphorylating and inhibiting the transcriptional activity of MEF2D. The cyclin-dependent kinases (CDKs) regulate cell cycle transitions and are activated at the appropriate time by the availability of their respective cyclins, depicted in the boxed inset. Cell cycle progression is achieved by the CDKs through the phosphorylation of Rb, which, when phosphorylated, is unable to bind and inhibit the E2F family of transcription factors that promote the expression of genes involved in cell division. Phosphorylation of Rb by the CDKs also prevents it from associating with and transactivating MyoD, thereby inhibiting cell cycle exit and differentiation. Cell cycle exit is further prevented by the proteolytic degradation of MyoD that results from direct CDK phosphorylation. The extracellular signal-regulated kinase (ERK) is activated by growth factors such as fibroblast growth factor and insulin-like growth factor (IGF), although the substrates ERK acts on to promote proliferation and inhibit differentiation are unknown. IGF also activates the Akt1 pathway and stimulates proliferation when myoblasts are subconfluent. Phosphorylation of FoxO1 by Akt1 prevents this transcription factor from accumulating in the nucleus, inhibiting the expression of genes involved in cell cycle exit, such as p27.

Regulation of the late myogenic transcriptional program by the kinome. The figure shows the mechanisms by which the kinases described in the text coordinate myoblast cell cycle exit, myoblast differentiation, myocyte fusion and myotube hypertrophy. Cell-cell contact and N-cadherin ligation, in conjunction with transforming growth factor-β-activated kinase 1 (TAK1) and MAP kinase kinase 3/6 (MKK), activate p38α. p38α induces cell cycle exit and differentiation through the phosphorylation of MEF2 and E47 that together with MyoD form part of an active myogenic transcriptional complex. A subunit of this complex is RNA polymerase II (RNA Pol II), which is phosphorylated and activated by cyclin-dependent kinase 9 (CDK9). Akt2, in response to IGF stimulation, phosphorylates the transcriptional coactivator and histone acetyltransferase p300, which is part of the same myogenic transcriptional complex. Activation of the Akt2 pathway promotes differentiation and hypertrophy by several other mechanisms as well. Akt2 phosphorylates and inactivates the FoxO family of transcription factors, whose activities are inhibitory to differentiation and hypertrophy. Phosphorylation of the mammalian target of rapamycin (mTOR) by Akt2 encourages protein synthesis/hypertrophy, partly through mTOR's phosphorylation and activation of the ribosomal protein S6 kinase 1 (S6K). Akt2 can also phosphorylate and inhibit glycogen synthase kinase 3β (GSK3). When active, GSK3 inhibits differentiation and hypertrophy through phosphorylation and cytoplasmic sequestration of NFATC3. Phosphorylation of β-catenin by GSK3 similarly prevents its nuclear accumulation and ability to activate the TCF/LEF family of transcription factors. Finally, activation of extracellular signal-regulated kinase 2 (ERK2) by an unknown stimulus promotes cell fusion through the phosphorylation and nuclear accumulation of NFAT3 via the 90-kDa ribosomal S6 kinase 2 (RSK2).