JAK-STAT pathway and myogenic differentiation

Figures & data

Figure 1. The steps of myogenic differentiation. Myoblasts originate from the mesoderm and are converted to skeletal muscle lineage myoblasts after MyoD and Myf5 expression. First, myoblasts enter the cell cycle and proliferate. When the growth factor or mitogen from myoblast cultures is withdrawn, proliferating cells exit from the cell cycle and initiate differentiation. Myogenin and MRF4 are involved in the initiation of differentiation. In this step, myoblasts changed to an elongated shape and are called myocytes. Myocytes fuse with neighboring cells into multinucleated myotubes. The multinucleated myotubes express the muscle specific proteins, MHC (myosin heavy chain), muscle creatine kinase (MCK) and α-actin. The mature form of myotubes is turned to myofiber.

Table 1. The JAKs-STATs family and associated components in regulation of myogenic proliferation and differentiation

	Proliferation	Differentiation
JAKs family	JAK1	JAK2, JAK3
STATs family	STAT1, STAT3	STAT2, STAT3, STAT1
Transcription factor	MEF2-STAT1 MyoD-STAT3*	MyoD-MEF2, MyoD-STAT3*(Fer?only in IGF stimulation)
Signaling pathway	MEK/ERK	PI3K/AKT
Negative regulator of STATs	SOCS1	SOCS1, SOCS3, PIAS1
Representative inducer	LIF	IGF

JAK1 activates STAT1 and STAT3, and activated STAT1 associates with transcription factor MEF2 in proliferation. Activated STAT3 interacts with MyoD, which inhibits differentiation and increases myoblast growth.* The MEK/ERK pathway is involved in this process. During proliferation, SOCS1, a negative regulator of STATs, is expressed, which inhibits differentiation of myoblasts. LIF induces proliferation and represses differentiation. In contrast, activation of JAK2 and inhibition of JAK3 promote differentiation. The activation of JAK2 phosphorylates STAT2 and STAT3 for differentiation. However, activation of JAK3 phosphorylates STAT1 and suppresses STAT3 activation, which inhibits differentiation. Activated STAT3 forms a complex with MyoD and the MyoD-MEF2 interaction, which stimulates transcription of MyoD- and MEF2-dependent muscle specific genes.* It is a mystery whether Fer, a mediator of STAT3 activity, is associated with this process. However, it is certain that the PI3K/AKT pathway contributes to differentiation, especially in IGF-induced myogenic differentiation. SOCS1, SOCS3 and PIAS inhibit activation of JAK1, gp130 and STAT1/3 binding to DNA, respectively. *Explains the dual effect of STAT3 on myoblast proliferation and differentiation.