JAK1-STAT1-STAT3, a key pathway promoting proliferation and preventing premature differentiation of myoblasts.
Skeletal muscle stem cell-derived myoblasts are mainly responsible for postnatal muscle growth and injury-induced muscle regeneration. However, the cellular signaling pathways controlling the proliferation and differentiation of myoblasts are not fully understood. We demonstrate that Janus kinase 1 (JAK1) is required for myoblast proliferation and that it also functions as a checkpoint to prevent myoblasts from premature differentiation. Deliberate knockdown of JAK1 in both primary and immortalized myoblasts induces precocious myogenic differentiation with a concomitant reduction in cell proliferation. This is caused, in part, by an accelerated induction of MyoD, myocyte enhancer-binding factor 2 (MEF2), p21Cip1, and p27Kip1, a faster down-regulation of Id1, and an increase in MEF2-dependent gene transcription. Downstream of JAK1, of all the signal transducer and activator of transcriptions (STATs) present in myoblasts, we find that only STAT1 knockdown promotes myogenic differentiation in both primary and immortalized myoblasts. Leukemia inhibitory factor stimulates myoblast proliferation and represses differentiation via JAK1-STAT1-STAT3. Thus, JAK1-STAT1-STAT3 constitutes a signaling pathway that promotes myoblast proliferation and prevents premature myoblast differentiation.
Sun
Luguo
L
Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, China.
Ma
Kewei
K
Wang
Haixia
H
Xiao
Fang
F
Gao
Yan
Y
Zhang
Wei
W
Wang
Kepeng
K
Gao
Xiang
X
Ip
Nancy
N
Wu
Zhenguo
Z
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018482:Muscle, Skeletal / Q000502:physiology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D018006:Myogenic Regulatory Factors; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1