MicroRNA-21 Regulates PI3K/Akt/mTOR Signaling by Targeting TGFβI during Skeletal Muscle Development in Pigs

Bai, Lijing; Liang, Ruyi; Yang, Yalan; Hou, Xinhua; Wang, Zishuai; Zhu, Shiyun; Wang, Chuduan; Tang, Zhonglin; Li, Kui

doi:10.1371/journal.pone.0119396

Cited by 62 publications

(54 citation statements)

References 49 publications

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“…52,53 Moreover, miR-21 targets TGF-b to regulate porcine skeletal muscle development through PI3K/Akt/mTOR signaling. 54 MiR-133 in myogenesis also functions through targeting insulin-like growth factor-1 receptor (IGF-1R) to down-regulate phosphorylation of Akt. 55 Given the fact that PI3K/Akt/mTOR pathway promotes myoblast differentiation and P55PIK is a participant of this pathway, we reason that during terminal differentiation, miR-432 may still use P55PIK as a target gene and exert inhibitory effects on myoblast differentiation through this pathway.…”

Section: ) (H and I) The Results Of Dual Luciferase Reporter Assaymentioning

confidence: 99%

MicroRNA-432 targeting E2F3 and P55PIK inhibits myogenesis through PI3K/AKT/mTOR signaling pathway

Wang

Chen

et al. 2017

RNA Biology

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Skeletal muscle is the dominant executant in locomotion and regulator in energy metabolism. Embryonic myogenesis and postnatal muscle growth are controlled by a cascade of transcription factors and epigenetic regulatory mechanisms. MicroRNAs (miRNAs), a family of non-coding RNA of 22 nucleotides in length, post-transcriptionally regulates expression of mRNA by pairing the seed sequence to 3 0 UTR of target mRNA. Increasing evidence has demonstrated that miRNAs are important regulators in diverse myogenic processes. The profiling of miRNA expression revealed that miR-432 is more enriched in the longissimus dorsi of 35-day-old piglets than that of adult pigs. Our gain of function study showed that miR-432 can negatively regulate both myoblast proliferation and differentiation. Mechanically, we found that miR-432 is able to down-regulate E2F transcription factor 3 (E2F3) to inactivate the expression of cell cycle and myogenic genes. We also identified that phosphatidylinositol 3-kinase regulatory subunit (P55PIK) is another target gene of miR-432 in muscle cells. downregulation of P55PIK by miR-432 leads to inhibition of P55PIK-mediated PI3K/AKT/mTOR signaling pathway during differentiation. The blocking effect of miR-432 on this pathway can be rescued by insulin treatment. Taken together, our findings identified microRNA-432 as a potent inhibitor of myogenesis which functions by targeting E2F3 and P55PIK in muscle cells.

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Section: ) (H and I) The Results Of Dual Luciferase Reporter Assaymentioning

confidence: 99%

MicroRNA-432 targeting E2F3 and P55PIK inhibits myogenesis through PI3K/AKT/mTOR signaling pathway

Wang

Chen

et al. 2017

RNA Biology

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“…Additionally, miR-21 has been shown to increase AKT/ mTORC1 signaling by inhibiting Treg differentiation [48,49]. MiR-21 has also been shown to regulate PI3K/AKT/mTOR signaling by targeting TGFβI gene expression [50]. Thus, miR-21 may also regulate Treg cell function through the regulation of the TGF-β/AKT/mTORC1 signaling pathway.…”

Section: Expression Levels Of Mir-21 Foxp3 Tgf-β1 and Smad7 In Pbmcmentioning

confidence: 99%

MicroRNA-21 Negatively Regulates Treg Cells Through a TGF-β1/Smad-Independent Pathway in Patients with Coronary Heart Disease

Fan

et al. 2015

Cell Physiol Biochem

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Background: CD4+CD25+FoxP3+ regulatory T cells (Treg cells) play a protective role against the development and progression of the inflammatory disease atherosclerosis (AS). MicroRNA-21 (miR-21) is expressed in Treg cells and is up-regulated in the context of AS and other inflammatory diseases. Aims: This study aimed to determine the role of miR-21 in Treg cell regulation and gene expression during the development of AS in patients with coronary heart disease (CHD). Methods and Results: MiR-21 expression in peripheral blood mononuclear cells (PBMCs) was significantly up-regulated in patients with CHD (acute myocardial infarction (AMI) group, n=24; unstable angina (UA) group, n=21; stable angina (SA) group, n=24) compared with patients with chest pain syndrome (CPS, n=27), and miR-21 expression showed an increasing trend from SA to UA to AMI patients. Moreover, flow cytometry analysis indicated that the frequencies of circulating Treg cells decreased in a manner proportionate opposite with the level of miR-21. Quantitative real-time PCR (qRT-PCR) revealed a decrease in mRNA expression of forkhead box P3 (foxp3), transforming cell growth factor beta 1(TGF-β1) and smad7 (a known target gene of miR-21). ELISA analysis revealed a decrease in TGF-β1 secreted into the plasma. In addition, we transfected PBMCs with a miRNA negative control (NS-m), a miR-21 mimic (miR-21-m), a miRNA inhibitor negative control (NS-i), or a miR-21 inhibitor(miR-21-i). Up-regulation of miR-21 decreased the frequency of circulating Treg cells, decreased the expression levels of foxp3, TGF-β1 and smad7, and decreased the amount of TGF-β1 secreted into the plasma. Consistent with these observations, miR-21 down-regulation increased the frequency of circulating Treg cells, increased the expression of foxp3, TGF-β1 and smad7, and increased the amount of TGF-β1 secreted into the plasma. Conclusions: Because the smad7 expression pattern was similar to that of TGF-β, our study suggests that miR-21 can negatively regulate the frequency of circulating Treg cells through a TGF-β1/smad-independent signaling pathway in PBMCs.

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“…Skeletal-muscle-specific miRNAs, including miR-1, miR-133, miR-206 and miR-208b/499 (Chen et al, 2006;Kim et al, 2006;McCarthy et al, 2009;Yang et al, 2015), muscleenriched miRNAs including miR-486 , and ubiquitous miRNAs including miR-21 (Bai et al, 2015) have all been shown to play important roles in myogenesis.…”

Section: Introductionmentioning

confidence: 99%

The NF-κB-modulated microRNAs miR-195 and miR-497 inhibit myoblast proliferation by targeting Igf1r, Insr and cyclin genes

Wei

Zhang

Bai

et al. 2016

Journal of Cell Science

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MicroRNAs (miRNAs) play important roles in the development of skeletal muscle. In our previous study, expression of miR-195 and miR-497 were shown to be upregulated during muscle development in pigs. In this study, we investigated the roles of these two miRNAs in myogenesis and analyzed their transcriptional regulation. Our results showed that miR-195 and miR-497 were upregulated during muscle development and myoblast differentiation. Moreover, miR-195 and miR-497 inhibited proliferation but not differentiation in C2C12 cells. Further investigation revealed that Igf1r, Insr, Ccnd2 and Ccne1 were directly targeted by miR-195 and miR-497 in myoblasts. In addition, we confirmed that miR-195 and miR-497, which shared the similar expression profiling, were negatively regulated by nuclear factor κB (NF-κB) in both myoblasts and skeletal muscle tissue. Our data illustrate that the signaling pathway NF-κB-miR-195/497-Igf1r/InsrCcnd2/Ccne1 plays important roles in myogenesis. Our study provides novel evidence for the roles of miR-195 and miR-497 in muscle development.

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MicroRNA-21 Regulates PI3K/Akt/mTOR Signaling by Targeting TGFβI during Skeletal Muscle Development in Pigs

Cited by 62 publications

References 49 publications

MicroRNA-432 targeting E2F3 and P55PIK inhibits myogenesis through PI3K/AKT/mTOR signaling pathway

MicroRNA-432 targeting E2F3 and P55PIK inhibits myogenesis through PI3K/AKT/mTOR signaling pathway

MicroRNA-21 Negatively Regulates Treg Cells Through a TGF-β1/Smad-Independent Pathway in Patients with Coronary Heart Disease

The NF-κB-modulated microRNAs miR-195 and miR-497 inhibit myoblast proliferation by targeting Igf1r, Insr and cyclin genes

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