scholarly journals p38 MAPK-induced Nuclear Factor-κB Activity Is Required for Skeletal Muscle Differentiation: Role of Interleukin-6

2004 ◽  
Vol 15 (4) ◽  
pp. 2013-2026 ◽  
Author(s):  
Bernat Baeza-Raja ◽  
Pura Muñoz-Cánoves
Keyword(s):  
Signaling Pathways ◽  
P38 Mapk ◽  
Myogenic Differentiation ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
Dependent Manner ◽  
Nuclear Factor

p38 MAPK and nuclear factor-κB (NF-κB) signaling pathways have been implicated in the control of skeletal myogenesis. However, although p38 is recognized as a potent activator of myoblast differentiation, the role of NF-κB remains controversial. Here, we show that p38 is activated only in differentiating myocytes, whereas NF-κB activity is present both in proliferation and differentiation stages. NF-κB activation was found to be dependent on p38 activity during differentiation, being NF-κB an effector of p38, thus providing a novel mechanism for the promyogenic effect of p38. Activation of p38 in C2C12 cells induced the activity of NF-κB, in a dual way: first, by reducing IκBα levels and inducing NF-κB-DNA binding activity and, second, by potentiating the transactivating activity of p65-NF-κB. Finally, we show that interleukin (IL)-6 expression is induced in C2C12 differentiating myoblasts, in a p38- and NF-κB-dependent manner. Interference of IL-6 mRNA reduced, whereas its overexpression increased, the extent of myogenic differentiation; moreover, addition of IL-6 was able to rescue significantly the negative effect of NF-κB inhibition on this process. This study provides the first evidence of a crosstalk between p38 MAPK and NF-κB signaling pathways during myogenesis, with IL-6 being one of the effectors of this promyogenic mechanism.

scholarly journals Dermatopontin in Skeletal Muscle Extracellular Matrix Regulates Myogenesis

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 332 ◽  
Author(s):  
Kim ◽  
Ahmad ◽  
Shaikh ◽  
Jan ◽  
Seo ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
In Silico ◽  
State Of The Art ◽  
Myogenic Differentiation ◽  
3D Structure ◽  
Inhibitory Effect ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
Protein Protein Interaction

Dermatopontin (DPT) is an extensively distributed non-collagenous component of the extracellular matrix predominantly found in the dermis of the skin, and consequently expressed in several tissues. In this study, we explored the role of DPT in myogenesis and perceived that it enhances the cell adhesion, reduces the cell proliferation and promotes the myoblast differentiation in C2C12 cells. Our results reveal an inhibitory effect with fibronectin (FN) in myoblast differentiation. We also observed that DPT and fibromodulin (FMOD) regulate positively to each other and promote myogenic differentiation. We further predicted the 3D structure of DPT, which is as yet unknown, and validated it using state-of-the-art in silico tools. Furthermore, we explored the in-silico protein-protein interaction between DPT-FMOD, DPT-FN, and FMOD-FN, and perceived that the interaction between FMOD-FN is more robust than DPT-FMOD and DPT-FN. Taken together, our findings have determined the role of DPT at different stages of the myogenic process.

scholarly journals Doxycycline Inhibits IL-17-Stimulated MMP-9 Expression by Downregulating ERK1/2 Activation: Implications in Myogenic Differentiation

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Hristina Obradović ◽  
Jelena Krstić ◽  
Tamara Kukolj ◽  
Drenka Trivanović ◽  
Ivana Okić Đorđević ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Myogenic Differentiation ◽  
C2c12 Cell ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
Interleukin 17 ◽  
Myoblast Cells ◽  
Pathological Consequence ◽  
Muscle Remodeling

Interleukin 17 (IL-17) is a cytokine with pleiotropic effects associated with several inflammatory diseases. Although elevated levels of IL-17 have been described in inflammatory myopathies, its role in muscle remodeling and regeneration is still unknown. Excessive extracellular matrix degradation in skeletal muscle is an important pathological consequence of many diseases involving muscle wasting. In this study, the role of IL-17 on the expression of matrix metalloproteinase- (MMP-) 9 in myoblast cells was investigated. The expression of MMP-9 after IL-17 treatment was analyzed in mouse myoblasts C2C12 cell line. The increase in MMP-9 production by IL-17 was concomitant with its capacity to inhibit myogenic differentiation of C2C12 cells. Doxycycline (Doxy) treatment protected the myogenic capacity of myoblasts from IL-17 inhibition and, moreover, increased myotubes hypertrophy. Doxy blocked the capacity of IL-17 to stimulate MMP-9 production by regulating IL-17-induced ERK1/2 MAPK activation. Our results imply that MMP-9 mediates IL-17’s capacity to inhibit myoblast differentiation during inflammatory diseases and indicate that Doxy can modulate myoblast response to inflammatory induction by IL-17.

Inhibition of Drp1-dependent mitochondrial division impairs myogenic differentiation

2013 ◽  
Vol 305 (8) ◽  
pp. R927-R938 ◽  
Author(s):  
Boa Kim ◽  
Ji-Seok Kim ◽  
Yisang Yoon ◽  
Mayra C. Santiago ◽  
Michael D. Brown ◽  
...  
Keyword(s):  
Muscle Development ◽  
Myogenic Differentiation ◽  
Mitochondrial Dynamics ◽  
C2c12 Cells ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Dominant Negative Mutant ◽  
Serum Starvation ◽  
Dependent Manner ◽  
Mitochondrial Division

Mitochondria are dynamic organelles forming a tubular network that is continuously fusing and dividing to control their morphology and functions. Recent literature has shed new light on a potential link between the dynamic behavior of mitochondria and muscle development. In this study, we investigate the role of mitochondrial fission factor dynamin-related protein 1 (Drp1) in myogenic differentiation. We found that differentiation of C2C12 myoblasts induced by serum starvation was accompanied by a gradual increase in Drp1 protein expression (to ∼350% up to 3 days) and a fast reduction of Drp1 phosphorylation at Ser-637 (to ∼30%) resulting in translocation of Drp1 protein from the cytosol to mitochondria. During differentiation, treatment of myoblasts with mitochondrial division inhibitor ( mdivi-1), a specific inhibitor of Drp1 GTPase activity, caused extensive formation of elongated mitochondria, which coincided with increased apoptosis evidenced by both enhanced caspase-3 activity and increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells. Furthermore, the mdivi-1-treated myotubes ( day 3 in differentiation media) showed a reduction in mitochondrial DNA content, mitochondrial mass, and membrane potential in a dose-dependent manner indicating defects in mitochondrial biogenesis during myogenic differentiation. Most interestingly, mdivi-1 treatment significantly suppressed myotube formation in both C2C12 cells and primary myoblasts. Likewise, stable overexpression of a dominant negative mutant Drp1 (K38A) dramatically reduced myogenic differentiation. These data suggest that Drp-1-dependent mitochondrial division is a necessary step for successful myogenic differentiation, and perturbation of mitochondrial dynamics hinders normal mitochondrial adaptations during muscle development. Therefore, in the present study, we report a novel physiological role of mitochondrial dynamics in myogenic differentiation.

Role of tumour necrosis factor receptor-1 and nuclear factor-κB in production of TNF-α-induced pro-inflammatory microparticles in endothelial cells

2014 ◽  
Vol 112 (09) ◽  
pp. 580-588 ◽  
Author(s):  
Sung Kyul Lee ◽  
Seung-Hee Yang ◽  
Il Kwon ◽  
Ok-Hee Lee ◽  
Ji Hoe Heo
Keyword(s):  
Endothelial Cells ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Necrosis Factor

SummaryTumour necrosis factor-α (TNF-α) is upregulated in many inflammatory diseases and is also a potent agent for microparticle (MP) generation. Here, we describe an essential role of TNF-α in the production of endothelial cell-derived microparticles (EMPs) in vivo and the function of TNF-α-induced EMPs in endothelial cells. We found that TNF-α rapidly increased blood levels of EMPs in mice. Treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α also induced EMP formation in a time-dependent manner. Silencing of TNF receptor (TNFR)-1 or inhibition of the nuclear factor-κB (NF-κB) in HUVECs impaired the production of TNF-α-induced EMP. Incubation of HUVECs with PKH-67-stained EMPs showed that endothelial cells readily engulfed EMPs, and the engulfed TNF-α-induced EMPs promoted the expression of pro-apoptotic molecules and upregulated intercellular adhesion molecule-1 level on the cell surface, which led to monocyte adhesion. Collectively, our findings indicate that the generation of TNF-α-induced EMPs was mediated by TNFR1 or NF-κB and that EMPs can contribute to apoptosis and inflammation of endothelial cells.

Abstract 17273: Long Non-Coding RNA Ppp1r1b Regulates Myogenic Differentiation Through Modulating Histone 3 Methylation

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Xuedong Kang ◽  
Yan Zhao ◽  
Marlin Touma
Keyword(s):  
Histone Modification ◽  
Protein Complex ◽  
Myogenic Differentiation ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
Mouse Heart ◽  
Histone 3

Introduction: Long noncoding RNAs (lncRNAs), emerged as critical epigenetic regulators of transcriptome, play important roles in cardiac development and might be targeted to treat human cardiomyocyte dysfunction. In our work, we identified a novel lncRNA that regulates myogenesis. Hypothesis: LncRNA Ppp1r1b regulates myogenesis by modulating Histone 3 methylation Methods: After treated with antisense oligonucleotides (GapmeR) or siRNA against Ppp1r1b-LncRNA, real time PCR and Western blot analyses were performed to examine the expression of myogenic and sarcomere genes. Chromatin immunoprecipitation (CHIP) was used to comparatively analyze gene specific histone modification level. RNA pull-down was employed to identify the protein molecules that interact with Ppp1r1b-LncRNA. Results: By silencing Ppp1r1b-LncRNA with GapmeR, C2C12, a skeletal myoblast cell line, did not develop fully differentiated myotubes, but tend to remain in a quiescent mono-nucleated status. In vivo analysis of GapmeR injected neonatal mouse heart and in vitro siRNA silenced human skeletal myoblasts further confirmed the important role of Ppp1r1b-LncRNA on myogenesis. Members of the MyoD family of muscle-specific transcription factors (MyoD and myogenin) failed to be up-regulated during myogenic differentiation when treated with Ppp1r1b-LncRNA specific GapmeR or siRNA. Key proteins essential for establishing and maintaining normal skeletal muscle architecture, including Tcap and Dystropnin, are also suppressed in Ppp1r1b LncRNA- deficient heart. Analysis of histone modification levels at Myogenin, MyoD1 and Tcap in C2C12 cells revealed more histone tri-methylation at these myogenic and sarcomere structural genes compared to untreated cells. Additional lncRNA- protein complex isolation has further revealed insight into the biological roles of Ppp1r1b-LncRNA. Conclusions: Our results support the role of Ppp1r1b-LncRNA in promoting myogenic differentiation. Ppp1r1b-lncRNA function is mediated by inhibiting histone methylation on promoters of multiple myogenic and sarcomere genes. In particular, the identification of EZH2 in pulled Pp1r1b LncRNA: protein complex implies that Polycomb repressive complex 2 (PRC2) is involved in Ppp1r1b-LncRNA modulated myoblast differentiation.

scholarly journals The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis

Blood ◽  
2011 ◽  
Vol 117 (5) ◽  
pp. 1652-1661 ◽  
Author(s):  
Jing Fu ◽  
Zhaoxia Qu ◽  
Pengrong Yan ◽  
Chie Ishikawa ◽  
Rami I. Aqeilan ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Signaling Pathways ◽  
Tumor Suppressor Gene ◽  
Nuclear Factor Κb ◽  
Suppressor Gene ◽  
Nuclear Factor ◽  
Mechanistic Studies ◽  
Viral Oncoprotein

Abstract Both the canonical and noncanonical nuclear factor κB (NF-κB) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-κB pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-κB activation was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-κB pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of κB kinaseα (IKKα) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKKα recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-κB pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-κB regulation and viral tumorigenesis.

scholarly journals A Novel Effect of Growth Hormone on Macrophage Modulates Macrophage-Dependent Adipocyte Differentiation

Endocrinology ◽  
2010 ◽  
Vol 151 (5) ◽  
pp. 2189-2199 ◽  
Author(s):  
Chunxia Lu ◽  
P. Anil Kumar ◽  
Yong Fan ◽  
Mark A. Sperling ◽  
Ram K. Menon
Keyword(s):  
Adipocyte Differentiation ◽  
Nuclear Factor Κb ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Preadipocyte Differentiation ◽  
Precise Role ◽  
Vascular Compartment ◽  
Specific Deletion

The GH receptor (GHR) is expressed on macrophages. However, the precise role of GH in regulation of macrophage function is unclear. We hypothesized that soluble factors including cytokines produced by macrophages in a GH-dependent manner regulate adipogenesis. We confirmed expression and functional integrity of the GHR in the J774A.1 macrophage cells. Conditioned medium (CM) from macrophages inhibited adipogenesis in a 3T3-L1 adipogenesis assay. CM from GH-treated macrophages decreased the inhibitory effect of CM from macrophages on adipogenesis. This effect on preadipocyte differentiation was active only during the first (early) phase of adipocyte differentiation. CM from stromal vascular compartment macrophages of mice with macrophage-specific deletion of the GHR exhibited more inhibitory effect on 3T3-L1 preadipocyte differentiation compared with CM from stromal vascular compartment macrophages of control mice, indicating that intact GH action in primary macrophages also increases preadipocyte differentiation. GH did not increase IGF-1 expression in macrophages. PCR array analysis identified IL-1β as a candidate cytokine whose expression was altered by GH in macrophages. Levels of IL-1β mRNA and protein were significantly decreased in GH-treated J774A.1 macrophages. Nuclear factor-κB stimulates IL-1β gene expression, and GH induced a significant decrease in the levels of phosphorylated nuclear factor-κB in macrophages. IL-1β is a known inhibitor of adipogenesis, and these results support GH-dependent down-regulation of macrophage IL-1β expression as one mechanism for the observed increase in adipogenesis with CM from GH-treated macrophages. We conclude that GH decreases secretion of IL-1β by the macrophage and thus in a paracrine manner increases adipocyte differentiation. These results provide a novel mechanism for GH’s actions in the control of adipogenesis.

Role of Thrombospondin-1 and Nuclear Factor-κB Signaling Pathways in Antiangiogenesis of Infantile Hemangioma

2018 ◽  
Vol 142 (3) ◽  
pp. 310e-321e ◽  
Author(s):  
Weili Xu ◽  
Suolin Li ◽  
Fengxue Yu ◽  
Yongting Zhang ◽  
Xiaofeng Yang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Infantile Hemangioma ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Thrombospondin 1

scholarly journals NF-κB, JNK, and TLR Signaling Pathways in Hepatocarcinogenesis

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Shin Maeda
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Inflammatory Cell ◽  
Prognostic Markers ◽  
Tumor Promotion ◽  
Neoplastic Cell ◽  
Nuclear Factor ◽  
Tlr Signaling ◽  
The Third

Hepatocellular carcinoma (HCC) is the third largest cause of cancer deaths worldwide. The role of molecular changes in HCC have been used to identify prognostic markers and chemopreventive or therapeutic targets. It seems that toll-like receptors (TLRs) as well as the nuclear factor (NF)-κB, and JNK pathways are critical regulators for the production of the cytokines associated with tumor promotion. The cross-talk between an inflammatory cell and a neoplastic cell, which is instigated by the activation of NF-κB and JNKs, is critical for tumor organization. JNKs also regulate cell proliferation and act as oncogenes, making them the main tumor-promoting protein kinases. TLRs play roles in cytokine and hepatomitogen expression mainly in myeloid cells and may promote liver tumorigenesis. A better understanding of these signaling pathways in the liver will help us understand the mechanism of hepatocarcinogenesis and provide a new therapeutic target for HCC.

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