scholarly journals Long noncoding RNASYISLregulates myogenesis by interacting with polycomb repressive complex 2

2018 ◽  
Vol 115 (42) ◽  
pp. E9802-E9811 ◽  
Author(s):  
Jian Jun Jin ◽  
Wei Lv ◽  
Pan Xia ◽  
Zai Yan Xu ◽  
An Dai Zheng ◽  
...  
Keyword(s):  
Muscle Development ◽  
Target Genes ◽  
Myogenic Differentiation ◽  
Expression Profiles ◽  
Myoblast Differentiation ◽  
C2c12 Myoblast ◽  
Polycomb Repressive Complex ◽  
Fiber Density ◽  
Muscle Creatine Kinase ◽  
Polycomb Repressive Complex 2

Although many long noncoding RNAs (lncRNAs) have been identified in muscle, their physiological function and regulatory mechanisms remain largely unexplored. In this study, we systematically characterized the expression profiles of lncRNAs during C2C12 myoblast differentiation and identified an intronic lncRNA,SYISL(SYNPO2intron sense-overlapping lncRNA), that is highly expressed in muscle. Functionally,SYISLpromotes myoblast proliferation and fusion but inhibits myogenic differentiation.SYISLknockout in mice results in significantly increased muscle fiber density and muscle mass. Mechanistically,SYISLrecruits the enhancer of zeste homolog 2 (EZH2) protein, the core component of polycomb repressive complex 2 (PRC2), to the promoters of the cell-cycle inhibitor genep21and muscle-specific genes such as myogenin (MyoG), muscle creatine kinase (MCK), and myosin heavy chain 4 (Myh4), leading to H3K27 trimethylation and epigenetic silencing of target genes. Taken together, our results reveal thatSYISLis a repressor of muscle development and plays a vital role in PRC2-mediated myogenesis.

scholarly journals The LIM-only protein FHL2 interacts with β-catenin and promotes differentiation of mouse myoblasts

2002 ◽  
Vol 159 (1) ◽  
pp. 113-122 ◽  
Author(s):  
Bernd Martin ◽  
Richard Schneider ◽  
Stefanie Janetzky ◽  
Zoe Waibler ◽  
Petra Pandur ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Muscle Development ◽  
Target Genes ◽  
Myogenic Differentiation ◽  
Myoblast Differentiation ◽  
Lim Domains ◽  
Vitro Binding ◽  
Specific Proteins

FHL2 is a LIM-domain protein expressed in myoblasts but down-regulated in malignant rhabdomyosarcoma cells, suggesting an important role of FHL2 in muscle development. To investigate the importance of FHL2 during myoblast differentiation, we performed a yeast two-hybrid screen using a cDNA library derived from myoblasts induced for differentiation. We identified β-catenin as a novel interaction partner of FHL2 and confirmed the specificity of association by direct in vitro binding tests and coimmunoprecipitation assays from cell lysates. Deletion analysis of both proteins revealed that the NH2-terminal part of β-catenin is sufficient for binding in yeast, but addition of the first armadillo repeat is necessary for binding FHL2 in mammalian cells, whereas the presence of all four LIM domains of FHL2 is needed for the interaction. Expression of FHL2 counteracts β-catenin–mediated activation of a TCF/LEF-dependent reporter gene in a dose-dependent and muscle cell–specific manner. After injection into Xenopus embryos, FHL2 inhibited the β-catenin–induced axis duplication. C2C12 mouse myoblasts stably expressing FHL2 show increased myogenic differentiation reflected by accelerated myotube formation and expression of muscle-specific proteins. These data imply that FHL2 is a muscle-specific repressor of LEF/TCF target genes and promotes myogenic differentiation by interacting with β-catenin.

Identification of the crucial molecular events during the large-scale myoblast fusion in sheep

2014 ◽  
Vol 46 (12) ◽  
pp. 429-440 ◽  
Author(s):  
Caihong Wei ◽  
Li Li ◽  
Hongwei Su ◽  
Lingyang Xu ◽  
Jian Lu ◽  
...  
Keyword(s):  
Large Scale ◽  
Molecular Mechanisms ◽  
Muscle Development ◽  
Target Genes ◽  
Myogenic Differentiation ◽  
Myoblast Fusion ◽  
Myoblast Differentiation ◽  
Pcr Analysis ◽  
Fetal Sheep ◽  
Fetal Muscle

It is well known that in sheep most myofibers are formed before birth; however, the crucial myogenic stage and the cellular and molecular mechanisms underpinning phenotypic variation of fetal muscle development remain to be ascertained. We used histological, microarray, and quantitative real-time PCR (qPCR) methods to examine the developmental characteristics of fetal muscle at 70, 85, 100, 120, and 135 days of gestation in sheep. We show that day 100 is an important checkpoint for change in muscle transcriptome and histomorphology in fetal sheep and that the period of 85–100 days is the vital developmental stage for large-scale myoblast fusion. Furthermore, we identified the cis-regulatory motifs for E2F1 or MEF2A in a list of decreasingly or increasingly expressed genes between 85 and 100 days, respectively. Further analysis demonstrated that the mRNA and phosphorylated protein levels of E2F1 and MEF2A significantly declined with myogenic progression in vivo and in vitro. qRT-PCR analysis indicated that PI3K and FST, as targets of E2F1, may be involved in myoblast differentiation and fusion and that downregulation of MEF2A contributes to transition of myofiber types by differential regulation of the target genes involved at the stage of 85–100 days. We clarify for the first time the timing of myofiber proliferation and development during gestation in sheep, which would be beneficial to meat sheep production. Our findings present a repertoire of gene expression in muscle during large-scale myoblast fusion at transcriptome-wide level, which contributes to elucidate the regulatory network of myogenic differentiation.

Wnt4 activates the canonical β-catenin pathway and regulates negatively myostatin: functional implication in myogenesis

2011 ◽  
Vol 300 (5) ◽  
pp. C1122-C1138 ◽  
Author(s):  
Henri Bernardi ◽  
Stephanie Gay ◽  
Yann Fedon ◽  
Barbara Vernus ◽  
Anne Bonnieu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Satellite Cells ◽  
Myogenic Differentiation ◽  
Expression Profiles ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
Strong Increase ◽  
C2c12 Myoblast ◽  
Wnt Proteins ◽  
Myogenic Activity

Expression of Wnt proteins is known to be important for developmental processes such as embryonic pattern formation and determination of cell fate. Previous studies have shown that Wn4 was involved in the myogenic fate of somites, in the myogenic proliferation, and differentiation of skeletal muscle. However, the function of this factor in adult muscle homeostasis remains not well understood. Here, we focus on the roles of Wnt4 during C2C12 myoblasts and satellite cells differentiation. We analyzed its myogenic activity, its mechanism of action, and its interaction with the anti-myogenic factor myostatin during differentiation. Established expression profiles indicate clearly that both types of cells express a few Wnts, and among these, only Wnt4 was not or barely detected during proliferation and was strongly induced during differentiation. As attested by myogenic factors expression pattern analysis and fusion index determination, overexpression of Wnt4 protein caused a strong increase in satellite cells and C2C12 myoblast differentiation leading to hypertrophic myotubes. By contrast, exposure of satellite and C2C12 cells to small interfering RNA against Wnt4 strongly diminished this process, confirming the myogenic activity of Wnt4. Moreover, we reported that Wnt4, which is usually described as a noncanonical Wnt, activates the canonical β-catenin pathway during myogenic differentiation in both cell types and that this factor regulates negatively the expression of myostatin and the regulating pathways associated with myostatin. Interestingly, we found that recombinant myostatin was sufficient to antagonize the differentiation-promoting activities of Wnt4. Reciprocally, we also found that the genetic deletion of myostatin renders the satellite cells refractory to the hypertrophic effect of Wnt4. These results suggest that the Wnt4-induced decrease of myostatin plays a functional role during hypertrophy. We propose that Wnt4 protein may be a key factor that regulates the extent of differentiation in satellite and C2C12 cells.

scholarly journals Rbm24 displays dynamic functions required for myogenic differentiation during muscle regeneration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raphaëlle Grifone ◽  
Audrey Saquet ◽  
Manon Desgres ◽  
Claudia Sangiorgi ◽  
Caterina Gargano ◽  
...  
Keyword(s):  
Muscle Regeneration ◽  
Muscle Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Myogenic Differentiation ◽  
Regulation Of Gene Expression ◽  
Repair Process ◽  
Myoblast Differentiation ◽  
C2c12 Myoblast ◽  
Adult Mice

AbstractSkeletal muscle has a remarkable capacity of regeneration after injury, but the regulatory network underlying this repair process remains elusive. RNA-binding proteins play key roles in the post-transcriptional regulation of gene expression and the maintenance of tissue homeostasis and plasticity. Rbm24 regulates myogenic differentiation during early development, but its implication in adult muscle is poorly understood. Here we show that it exerts multiple functions in muscle regeneration. Consistent with its dynamic subcellular localization during embryonic muscle development, Rbm24 also displays cytoplasm to nucleus translocation during C2C12 myoblast differentiation. In adult mice, Rbm24 mRNA is enriched in slow-twitch muscles along with myogenin mRNA. The protein displays nuclear localization in both slow and fast myofibers. Upon injury, Rbm24 is rapidly upregulated in regenerating myofibers and accumulates in the myonucleus of nascent myofibers. Through satellite cell transplantation, we demonstrate that Rbm24 functions sequentially to regulate myogenic differentiation and muscle regeneration. It is required for myogenin expression at early stages of muscle injury and for muscle-specific pre-mRNA alternative splicing at late stages of regeneration. These results identify Rbm24 as a multifaceted regulator of myoblast differentiation. They provide insights into the molecular pathway orchestrating the expression of myogenic factors and muscle functional proteins during regeneration.

scholarly journals Myoferlin Regulates Wnt/β-Catenin Signaling-Mediated Skeletal Muscle Development by Stabilizing Dishevelled-2 Against Autophagy

2019 ◽  
Vol 20 (20) ◽  
pp. 5130 ◽  
Author(s):  
Shunshun Han ◽  
Can Cui ◽  
Haorong He ◽  
Xiaoxu Shen ◽  
Yuqi Chen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Development ◽  
Skeletal Muscle Atrophy ◽  
Myoblast Differentiation ◽  
C2c12 Myoblast ◽  
Skeletal Muscle Development ◽  
Muscle Tissues ◽  
Underlying Mechanisms ◽  
Canonical Wnt

Myoferlin (MyoF), which is a calcium/phospholipid-binding protein expressed in cardiac and muscle tissues, belongs to the ferlin family. While MyoF promotes myoblast differentiation, the underlying mechanisms remain poorly understood. Here, we found that MyoF not only promotes C2C12 myoblast differentiation, but also inhibits muscle atrophy and autophagy. In the present study, we found that myoblasts fail to develop into mature myotubes due to defective differentiation in the absence of MyoF. Meanwhile, MyoF regulates the expression of atrophy-related genes (Atrogin-1 and MuRF1) to rescue muscle atrophy. Furthermore, MyoF interacts with Dishevelled-2 (Dvl-2) to activate canonical Wnt signaling. MyoF facilitates Dvl-2 ubiquitination resistance by reducing LC3-labeled Dvl-2 levels and antagonizing the autophagy system. In conclusion, we found that MyoF plays an important role in myoblast differentiation during skeletal muscle atrophy. At the molecular level, MyoF protects Dvl-2 against autophagy-mediated degradation, thus promoting activation of the Wnt/β-catenin signaling pathway. Together, our findings suggest that MyoF, through stabilizing Dvl-2 and preventing autophagy, regulates Wnt/β-catenin signaling-mediated skeletal muscle development.

scholarly journals p57Kip2 Stabilizes the MyoD Protein by Inhibiting Cyclin E-Cdk2 Kinase Activity in Growing Myoblasts

1999 ◽  
Vol 19 (11) ◽  
pp. 7621-7629 ◽  
Author(s):  
Emmanuel G. Reynaud ◽  
Karine Pelpel ◽  
Martine Guillier ◽  
Marie Pierre Leibovitch ◽  
Serge A. Leibovitch
Keyword(s):  
Cyclin E ◽  
Tight Binding ◽  
Dominant Negative ◽  
Myoblast Differentiation ◽  
C2c12 Myoblast ◽  
Cdk Inhibitors ◽  
Cyclin Dependent Kinase ◽  
Muscle Creatine Kinase ◽  
Mouse Muscle ◽  
Cdk2 Activity

ABSTRACT We show that expression of p57Kip2, a potent tight-binding inhibitor of several G1cyclin–cyclin-dependent kinase (Cdk) complexes, increases markedly during C2C12 myoblast differentiation. We examined the effect of p57Kip2 on the activity of the transcription factor MyoD. In transient transfection assays, transcriptional transactivation of the mouse muscle creatine kinase promoter by MyoD was enhanced by the Cdk inhibitors. In addition, p57Kip2, p21Cip1, and p27Kip1 but not p16Ink4a induced an increased level of MyoD protein, and we show that MyoD, an unstable nuclear protein, was stabilized by p57Kip2. Forced expression of p57Kip2 correlated with hypophosphorylation of MyoD in C2C12 myoblasts. A dominant-negative Cdk2 mutant arrested cells at the G1 phase transition and induced hypophosphorylation of MyoD. Furthermore, phosphorylation of MyoD by purified cyclin E-Cdk2 complexes was inhibited by p57Kip2. In addition, the NH2 domain of p57Kip2 necessary for inhibition of cyclin E-Cdk2 activity was sufficient to inhibit MyoD phosphorylation and to stabilize it, leading to its accumulation in proliferative myoblasts. Taken together, our data suggest that repression of cyclin E-Cdk2-mediated phosphorylation of MyoD by p57Kip2 could play an important role in the accumulation of MyoD at the onset of myoblast differentiation.

scholarly journals IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients

2003 ◽  
Vol 163 (5) ◽  
pp. 931-936 ◽  
Author(s):  
Ebru Erbay ◽  
In-Hyun Park ◽  
Paul D. Nuzzi ◽  
Christopher J. Schoenherr ◽  
Jie Chen
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Kinase Activity ◽  
Regulatory Elements ◽  
Myoblast Differentiation ◽  
Akt Pathway ◽  
C2c12 Myoblast ◽  
Skeletal Muscle Development ◽  
Primary Target ◽  
Insulin Like Growth Factors

Insulin-like growth factors (IGFs) are essential for skeletal muscle development, regeneration, and hypertrophy. Although autocrine actions of IGF-II are known to initiate myoblast differentiation, the regulatory elements and upstream signaling pathways for myogenic expression of IGF-II remain elusive. Here, we report the regulation of IGF-II transcription by mTOR, as well as by amino acid sufficiency, through the IGF-II promoter 3 and a downstream enhancer during C2C12 myoblast differentiation. Furthermore, we present evidence that IGF production, and not IGF signaling, is the primary target for mTOR's function in the initiation of differentiation. Moreover, myogenic signaling by mTOR is independent of its kinase activity and mediated by the PI3K–Akt pathway. Our findings represent the first identification of a signaling pathway that regulates IGF-II expression in myogenesis and implicate the mTOR–IGF axis as a molecular link between nutritional levels and skeletal muscle development.

scholarly journals Ganoderma microsporum immunomodulatory protein, GMI, promotes C2C12 myoblast differentiation in vitro via upregulation of Tid1 and STAT3 acetylation

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244791
Author(s):  
Wan-Huai Teo ◽  
Jeng-Fan Lo ◽  
Yu-Ning Fan ◽  
Chih-Yang Huang ◽  
Tung-Fu Huang
Keyword(s):  
Myogenic Differentiation ◽  
Atp Synthesis ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
C2c12 Myoblast ◽  
Muscle Loss ◽  
C2c12 Myoblasts ◽  
Immunomodulatory Protein ◽  
Pre Treatment

Ageing and chronic diseases lead to muscle loss and impair the regeneration of skeletal muscle. Thus, it’s crucial to seek for effective intervention to improve the muscle regeneration. Tid1, a mitochondrial co-chaperone, is important to maintain mitochondrial membrane potential and ATP synthesis. Previously, we demonstrated that mice with skeletal muscular specific Tid1 deficiency displayed muscular dystrophy and postnatal lethality. Tid1 can interact with STAT3 protein, which also plays an important role during myogenesis. In this study, we used GMI, immunomodulatory protein of Ganoderma microsporum, as an inducer in C2C12 myoblast differentiation. We observed that GMI pretreatment promoted the myogenic differentiation of C2C12 myoblasts. We also showed that the upregulation of mitochondria protein Tid1 with the GMI pre-treatment promoted myogenic differentiation ability of C2C12 cells. Strikingly, we observed the concomitant elevation of STAT3 acetylation (Ac-STAT3) during C2C12 myogenesis. Our study suggests that GMI promotes the myogenic differentiation through the activation of Tid1 and Ac-STAT3.

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