title: Role of JAK3 in myogenic differentiation.
abstract: Skeletal muscle differentiation is regulated by transcription factors, including members of the myogenic regulatory factor (MRF) family and many signaling pathways. The JAK1 and JAK2 pathways are known to each have different effects on myoblast proliferation and differentiation; however, the role of JAK3 in myoblast differentiation remains unclear. In this study, we investigated the effect of JAK3 inhibition on myogenic differentiation in the C2C12 mouse myoblast cell line. During myogenic differentiation, treatment with the JAK3 inhibitor WHIp154 significantly increased the number of MHC-positive multinucleated myotubes and the expressions of myosin heavy chain (MHC), myogenin (MGN), MyoD, and myogenic enhancer factor 2 (MEF2). Knockdown of the JAK3 gene using siJAK3 also significantly increased MHC, MGN and MyoD mRNA expressions as well as insulin-like growth factor-II (IGF-II) gene expression. During differentiation, JAK3 was initially activated and later decreased. Differentiation decreased STAT1, which was further decreased by WHIp154. In contrast, STAT3 gradually was elevated during differentiation, and was increased by JAK3 inhibition. Moreover, we found that up-regulation of AKT activity and down-regulation of ERK activity cooperated to accelerate myogenic differentiation. Taken together, these data indicate that JAK3 inhibition potently facilitates myoblast differentiation through antagonistic STAT1/STAT3 activities. Additionally, JAK3 inhibition induced precocious differentiation and played important roles for terminal differentiation, including fusion, which is involved with regulation of AKT and ERK pathways.
authors: Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.
authors: You-Na
authors: YN
authors: Jang
authors: Il Jae
authors: IJ
authors: Lee
authors: Myong Chul
authors: MC
authors: Park
authors: Eun Joo
authors: EJ
authors: Baik
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000201:enzymology*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D017570:MyoD Protein; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D011799:Quinazolines; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C113888:WHI P154; D007335:Insulin-Like Growth Factor II; D053616:Janus Kinase 3; D018995:Myosin Heavy Chains