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¹ Department of Biochemistry, Hong Kong University of Science and Technology, Hong Kong, China
² Model Animal Research Center, Nanjing University, Nanjing 210061, China

Correspondence to Zhenguo Wu: bczgwu{at}ust.hk

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.

L. Sun and K. Ma contributed equally to this paper.

L. Sun's and K. Ma's present address is The First Clinical Hospital, Jilin University, Changchun 130021, China.

Abbreviations used in this paper: DM, differentiation medium; EMSA, electro-phoretic mobility shift assay; ERK, extracellular signal-regulated kinase; GM, growth medium; JAK, Janus kinase; LIF, leukemia inhibitory factor; MCK, muscle creatine kinase; MEF2, myocyte enhancer–binding factor 2; MHC, myosin heavy chain; MRF, myogenic regulatory factor; MSC, muscle satellite cell; shRNA, short hairpin RNA; STAT, signal transducer and activator of transcription; TA, tibialis anterior; WCE, whole cell extract.

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• Wang, K., Wang, C., Xiao, F., Wang, H., Wu, Z. (2008). JAK2/STAT2/STAT3 Are Required for Myogenic Differentiation. J. Biol. Chem. 283: 34029-34036 [Abstract] [Full Text]  
• Alter, J., Rozentzweig, D., Bengal, E. (2008). Inhibition of Myoblast Differentiation by Tumor Necrosis Factor {alpha} Is Mediated by c-Jun N-terminal Kinase 1 and Leukemia Inhibitory Factor. J. Biol. Chem. 283: 23224-23234 [Abstract] [Full Text]  

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