Attenuation of p38-mediated miR-1/133 expression facilitates myoblast proliferation during the early stage of muscle regeneration.
Myoblast proliferation following myotrauma is regulated by multiple factors including growth factors, signal pathways, transcription factors, and miRNAs. However, the molecular mechanisms underlying the orchestration of these regulatory factors remain unclear. Here we show that p38 signaling is required for miR-1/133a clusters transcription and both p38 activity and miR-1/133 expression are attenuated during the early stage of muscle regeneration in various animal models. Additionally, we show that both miR-1 and miR-133 reduce Cyclin D1 expression and repress myoblast proliferation by inducing G1 phase arrest. Furthermore, we demonstrate that miR-133 inhibits mitotic progression by targeting Sp1, which mediates Cyclin D1 transcription, while miR-1 suppresses G1/S phase transition by targeting Cyclin D1. Finally, we reveal that proproliferative FGF2, which is elevated during muscle regeneration, attenuates p38 signaling and miR-1/133 expression. Taken together, our results suggest that downregulation of p38-mediated miR-1/133 expression by FGF2 and subsequent upregulation of Sp1/Cyclin D1 contribute to the increased myoblast proliferation during the early stage of muscle regeneration.
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Duo
D
Zhang
Xihua
X
Li
Chuchu
C
Chen
Yuyin
Y
Li
Lei
L
Zhao
Yanyan
Y
Jing
Wei
W
Liu
Xiaoyun
X
Wang
Ying
Y
Zhang
Hongfeng
H
Xia
Yaning
Y
Chang
Xiang
X
Gao
Jun
J
Yan
Hao
H
Ying
D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D009132:Muscles / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology* / Q000201:enzymology*; D012038:Regeneration / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; C517732:Mirn133 microRNA, mouse; D016329:Sp1 Transcription Factor; D016222:Fibroblast Growth Factor 2; D019938:Cyclin D1; D048051:p38 Mitogen-Activated Protein Kinases