scholarly journals TRAIL/DR5 pathway promotes AKT phosphorylation, skeletal muscle differentiation, and glucose uptake

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Barbara Toffoli ◽  
Federica Tonon ◽  
Veronica Tisato ◽  
Giorgio Zauli ◽  
Paola Secchiero ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Therapeutic Potential ◽  
Myogenic Differentiation ◽  
Body Weight Gain ◽  
Muscle Differentiation ◽  
C2c12 Cells ◽  
Acid Oxidation ◽  
Skeletal Muscle Differentiation ◽  
Akt Phosphorylation

AbstractTNF-related apoptosis-inducing ligand (TRAIL) is a protein that induces apoptosis in cancer cells but not in normal ones, where its effects remain to be fully understood. Previous studies have shown that in high-fat diet (HFD)-fed mice, TRAIL treatment reduced body weight gain, insulin resistance, and inflammation. TRAIL was also able to increase skeletal muscle free fatty acid oxidation. The aim of the present work was to evaluate TRAIL actions on skeletal muscle. Our in vitro data on C2C12 cells showed that TRAIL treatment significantly increased myogenin and MyHC and other hallmarks of myogenic differentiation, which were reduced by Dr5 (TRAIL receptor) silencing. In addition, TRAIL treatment significantly increased AKT phosphorylation, which was reduced by Dr5 silencing, as well as glucose uptake (alone and in combination with insulin). Our in vivo data showed that TRAIL increased myofiber size in HFD-fed mice as well as in db/db mice. This was associated with increased myogenin and PCG1α expression. In conclusion, TRAIL/DR5 pathway promotes AKT phosphorylation, skeletal muscle differentiation, and glucose uptake. These data shed light onto a pathway that might hold therapeutic potential not only for the metabolic disturbances but also for the muscle mass loss that are associated with diabetes.

scholarly journals 6-Bromoindirubin-3′-oxime intercepts GSK3 signaling to promote and enhance skeletal muscle differentiation affecting miR-206 expression in mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Elvira Ragozzino ◽  
Mariarita Brancaccio ◽  
Antonella Di Costanzo ◽  
Francesco Scalabrì ◽  
Gennaro Andolfi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Myogenic Differentiation ◽  
Muscle Differentiation ◽  
C2c12 Cells ◽  
Skeletal Muscle Differentiation ◽  
Myoblast Proliferation ◽  
Enhanced Expression ◽  
Pharmacologically Active

AbstractDystrophies are characterized by progressive skeletal muscle degeneration and weakness as consequence of their molecular abnormalities. Thus, new drugs for restoring skeletal muscle deterioration are critically needed. To identify new and alternative compounds with a functional role in skeletal muscle myogenesis, we screened a library of pharmacologically active compounds and selected the small molecule 6-bromoindirubin-3′-oxime (BIO) as an inhibitor of myoblast proliferation. Using C2C12 cells, we examined BIO’s effect during myoblast proliferation and differentiation showing that BIO treatment promotes transition from cell proliferation to myogenic differentiation through the arrest of cell cycle. Here, we show that BIO is able to promote myogenic differentiation in damaged myotubes in-vitro by enriching the population of newly formed skeletal muscle myotubes. Moreover, in-vivo experiments in CTX-damaged TA muscle confirmed the pro-differentiation capability of BIO as shown by the increasing of the percentage of myofibers with centralized nuclei as well as by the increasing of myofibers number. Additionally, we have identified a strong correlation of miR-206 with BIO treatment both in-vitro and in-vivo: the enhanced expression of miR-206 was observed in-vitro in BIO-treated proliferating myoblasts, miR-206 restored expression was observed in a forced miR-206 silencing conditions antagomiR-mediated upon BIO treatment, and in-vivo in CTX-injured muscles miR-206 enhanced expression was observed upon BIO treatment. Taken together, our results highlight the capacity of BIO to act as a positive modulator of skeletal muscle differentiation in-vitro and in-vivo opening up a new perspective for novel therapeutic targets to correct skeletal muscle defects.

scholarly journals Coordinated Vascular Endothelial Growth Factor Expression and Signaling During Skeletal Myogenic Differentiation

2008 ◽  
Vol 19 (3) ◽  
pp. 994-1006 ◽  
Author(s):  
Brad A. Bryan ◽  
Tony E. Walshe ◽  
Dianne C. Mitchell ◽  
Josh S. Havumaki ◽  
Magali Saint-Geniez ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Myogenic Differentiation ◽  
Es Cells ◽  
Muscle Differentiation ◽  
C2c12 Cells ◽  
Vascular Endothelial ◽  
Skeletal Muscle Differentiation ◽  
Endothelial Growth Factor

Angiogenesis is largely controlled by hypoxia-driven transcriptional up-regulation and secretion of vascular endothelial growth factor (VEGF) and its binding to the endothelial cell tyrosine receptor kinases, VEGFR1 and VEGFR2. Recent expression analysis suggests that VEGF is expressed in a cell-specific manner in normoxic adult tissue; however, the transcriptional regulation and role of VEGF in these tissues remains fundamentally unknown. In this report we demonstrate that VEGF is coordinately up-regulated during terminal skeletal muscle differentiation. We reveal that this regulation is mediated in part by MyoD homo- and hetero-dimeric transcriptional mechanisms. Serial deletions of the VEGF promoter elucidated a region containing three tandem CANNTG consensus MyoD sites serving as essential sites of direct interaction for MyoD-mediated up-regulation of VEGF transcription. VEGF-null embryonic stem (ES) cells exhibited reduced myogenic differentiation compared with wild-type ES cells, suggesting that VEGF may serve a role in skeletal muscle differentiation. We demonstrate that VEGFR1 and VEGFR2 are expressed at low levels in myogenic precursor cells and are robustly activated upon VEGF stimulation and that their expression is coordinately regulated during skeletal muscle differentiation. VEGF stimulation of differentiating C2C12 cells promoted myotube hypertrophy and increased myogenic differentiation, whereas addition of sFlt1, a VEGF inhibitor, resulted in myotube hypotrophy and inhibited myogenic differentiation. We further provide evidence indicating VEGF-mediated myogenic marker expression, mitogenic activity, migration, and prosurvival functions may contribute to increased myogenesis. These data suggest a novel mechanism whereby VEGF is coordinately regulated as part of the myogenic differentiation program and serves an autocrine function regulating skeletal myogenesis.

scholarly journals Inositide-Dependent Phospholipase C Signaling Mimics Insulin in Skeletal Muscle Differentiation by Affecting Specific Regions of the Cyclin D3 Promoter

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1108-1117 ◽  
Author(s):  
Irene Faenza ◽  
Giulia Ramazzotti ◽  
Alberto Bavelloni ◽  
Roberta Fiume ◽  
Gian Carlo Gaboardi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Phospholipase C ◽  
Myogenic Differentiation ◽  
Muscle Differentiation ◽  
C2c12 Cells ◽  
Cyclin D3 ◽  
Expression Vectors ◽  
Skeletal Muscle Differentiation ◽  
Small Interfering Rnas

Our main goal in this study was to investigate the role of phospholipase C (PLC) β1 and PLCγ1 in skeletal muscle differentiation and the existence of potential downstream targets of their signaling activity. To examine whether PLC signaling can modulate the expression of cyclin D3, a target of PLCβ1 in erythroleukemia cells, we transfected C2C12 cells with expression vectors containing PLCβ1 or PLCγ1 cDNA and with small interfering RNAs from regions of the PLCβ1 or PLCγ1 gene and followed myogenic differentiation in this well-established cell system. Intriguingly, overexpressed PLCβ1 and PLCγ1 were able to mimic insulin induction of both cyclin D3 and muscle differentiation. By knocking down PLCβ1 or PLCγ1 expression, C2C12 cells almost completely lost the increase in cyclin D3, and the differentiation program was down-regulated. To explore the induction of the cyclin D3 gene promoter during this process, we used a series of 5′-deletions of the 1.68-kb promoter linked to a reporter gene and noted a 5-fold augmentation of promoter activity upon insulin stimulation. These constructs were also cotransfected with PLCβ1 or PLCγ1 cDNAs and small interfering RNAs, respectively. Our data indicate that PLCβ1 or PLCγ1 signaling is capable of acting like insulin in regard to both the myogenic differentiation program and cyclin D3 up-regulation. Taken together, this is the first study that hints at cyclin D3 as a target of PLCβ1 and PLCγ1 during myogenic differentiation in vitro and implies that up-regulation of these enzymes is sufficient to mimic the actions of insulin in this process.

scholarly journals Zfp422 promotes skeletal muscle differentiation by regulating EphA7 to induce appropriate myoblast apoptosis

2019 ◽  
Vol 27 (5) ◽  
pp. 1644-1659 ◽  
Author(s):  
Yaping Nie ◽  
Shufang Cai ◽  
Renqiang Yuan ◽  
Suying Ding ◽  
Xumeng Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Zinc Finger ◽  
Muscle Development ◽  
Zinc Finger Protein ◽  
Critical Role ◽  
Muscle Differentiation ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Finger Protein

Abstract Zinc finger protein 422 (Zfp422) is a widely expressed zinc finger protein that serves as a transcriptional factor to regulate downstream gene expression, but until now, little is known about its roles in myogenesis. We found here that Zfp422 plays a critical role in skeletal muscle development and regeneration. It highly expresses in mouse skeletal muscle during embryonic development. Specific knockout of Zfp422 in skeletal muscle impaired embryonic muscle formation. Satellite cell-specific Zfp422 deletion severely inhibited muscle regeneration. Myoblast differentiation and myotube formation were suppressed in Zfp422-deleted C2C12 cells, isolated primary myoblasts, and satellite cells. Chromatin Immunoprecipitation Sequencing (ChIP-Seq) revealed that Zfp422 regulated ephrin type-A receptor 7 (EphA7) expression by binding an upstream 169-bp DNA sequence, which was proved to be an enhancer of EphA7. Knocking EphA7 down in C2C12 cells or deleting Zfp422 in myoblasts will inhibit cell apoptosis which is required for myoblast differentiation. These results indicate that Zfp422 is essential for skeletal muscle differentiation and fusion, through regulating EphA7 expression to maintain proper apoptosis.

scholarly journals New Intracellular Peptide Derived from Hemoglobin Alpha Chain Induces Glucose Uptake and Reduces Blood Glycemia

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2175
Author(s):  
Renée N. O. Silva ◽  
Ricardo P. Llanos ◽  
Rosangela A. S. Eichler ◽  
Thiago B. Oliveira ◽  
Fábio C. Gozzo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Knockout Mice ◽  
Conditional Knockout ◽  
C2c12 Cells ◽  
Yeast Cells ◽  
Epididymal Adipose Tissue ◽  
Mrna Levels ◽  
Akt Phosphorylation

Intracellular peptides were shown to derive from proteasomal degradation of proteins from mammalian and yeast cells, being suggested to play distinctive roles both inside and outside these cells. Here, the role of intracellular peptides previously identified from skeletal muscle and adipose tissues of C57BL6/N wild type (WT) and neurolysin knockout mice were investigated. In differentiated C2C12 mouse skeletal muscle cells, some of these intracellular peptides like insulin activated the expression of several genes related to muscle contraction and gluconeogenesis. One of these peptides, LASVSTVLTSKYR (Ric4; 600 µg/kg), administrated either intraperitoneally or orally in WT mice, decreased glycemia. Neither insulin (10 nM) nor Ric4 (100 µM) induced glucose uptake in adipose tissue explants obtained from conditional knockout mice depleted of insulin receptor. Ric4 (100 µM) similarly to insulin (100 nM) induced Glut4 translocation to the plasma membrane of C2C12 differentiated cells, and increased GLUT4 mRNA levels in epididymal adipose tissue of WT mice. Ric4 (100 µM) increased both Erk and Akt phosphorylation in C2C12, as well as in epididymal adipose tissue from WT mice; Erk, but not Akt phosphorylation was activated by Ric4 in tibial skeletal muscle from WT mice. Ric4 is rapidly degraded in vitro by WT liver and kidney crude extracts, such a response that is largely reduced by structural modifications such as N-terminal acetylation, C-terminal amidation, and substitution of Leu8 for DLeu8 (Ac-LASVSTV[DLeu]TSKYR-NH2; Ric4-16). Ric4-16, among several Ric4 derivatives, efficiently induced glucose uptake in differentiated C2C12 cells. Among six Ric4-derivatives evaluated in vivo, Ac-LASVSTVLTSKYR-NH2 (Ric4-2; 600 µg/kg) and Ac-LASVSTV[DLeu]TSKYR (Ric4-15; 600 µg/kg) administrated orally efficiently reduced glycemia in a glucose tolerance test in WT mice. The potential clinical application of Ric4 and Ric4-derivatives deserves further attention.

scholarly journals Zeb2 Regulates Myogenic Differentiation in Pluripotent Stem Cells

2020 ◽  
Vol 21 (7) ◽  
pp. 2525
Author(s):  
Ester Sara Di Filippo ◽  
Domiziana Costamagna ◽  
Giorgia Giacomazzi ◽  
Álvaro Cortés-Calabuig ◽  
Agata Stryjewska ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Transcription Factors ◽  
Zinc Finger ◽  
Pluripotent Stem Cells ◽  
Myogenic Differentiation ◽  
Muscle Differentiation ◽  
Skeletal Muscle Regeneration ◽  
Skeletal Muscle Differentiation ◽  
E Box

Skeletal muscle differentiation is triggered by a unique family of myogenic basic helix-loop-helix transcription factors, including MyoD, MRF-4, Myf-5, and Myogenin. These transcription factors bind promoters and distant regulatory regions, including E-box elements, of genes whose expression is restricted to muscle cells. Other E-box binding zinc finger proteins target the same DNA response elements, however, their function in muscle development and regeneration is still unknown. Here, we show that the transcription factor zinc finger E-box-binding homeobox 2 (Zeb2, Sip-1, Zfhx1b) is present in skeletal muscle tissues. We investigate the role of Zeb2 in skeletal muscle differentiation using genetic tools and transgenic mouse embryonic stem cells, together with single-cell RNA-sequencing and in vivo muscle engraftment capability. We show that Zeb2 over-expression has a positive impact on skeletal muscle differentiation in pluripotent stem cells and adult myogenic progenitors. We therefore propose that Zeb2 is a novel myogenic regulator and a possible target for improving skeletal muscle regeneration. The non-neural roles of Zeb2 are poorly understood.

scholarly journals The SMYD3 methyltransferase promotes myogenesis by activating the myogenin regulatory network

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Roberta Codato ◽  
Martine Perichon ◽  
Arnaud Divol ◽  
Ella Fung ◽  
Athanassia Sotiropoulos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Myogenic Differentiation ◽  
Muscle Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Skeletal Muscle Development ◽  
Genome Wide ◽  
Coordinated Expression

AbstractThe coordinated expression of myogenic regulatory factors, including MyoD and myogenin, orchestrates the steps of skeletal muscle development, from myoblast proliferation and cell-cycle exit, to myoblast fusion and myotubes maturation. Yet, it remains unclear how key transcription factors and epigenetic enzymes cooperate to guide myogenic differentiation. Proteins of the SMYD (SET and MYND domain-containing) methyltransferase family participate in cardiac and skeletal myogenesis during development in zebrafish, Drosophila and mice. Here, we show that the mammalian SMYD3 methyltransferase coordinates skeletal muscle differentiation in vitro. Overexpression of SMYD3 in myoblasts promoted muscle differentiation and myoblasts fusion. Conversely, silencing of endogenous SMYD3 or its pharmacological inhibition impaired muscle differentiation. Genome-wide transcriptomic analysis of murine myoblasts, with silenced or overexpressed SMYD3, revealed that SMYD3 impacts skeletal muscle differentiation by targeting the key muscle regulatory factor myogenin. The role of SMYD3 in the regulation of skeletal muscle differentiation and myotube formation, partially via the myogenin transcriptional network, highlights the importance of methyltransferases in mammalian myogenesis.

scholarly journals IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts

2019 ◽  
Vol 21 (1) ◽  
pp. 182 ◽  
Author(s):  
Yukako Tokutake ◽  
Keita Yamada ◽  
Satoko Hayashi ◽  
Wataru Arai ◽  
Takafumi Watanabe ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Differentiation ◽  
C2c12 Cells ◽  
Myoblast Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Cyclin Dependent Kinase ◽  
Early Differentiation ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

In skeletal muscle, myoblast differentiation results in the formation of multinucleated myofibers. Although recent studies have shown that unfolded protein responses (UPRs) play an important role in intracellular remodeling and contribute to skeletal muscle differentiation, the involvement of IRE1–XBP1 signaling, a major UPR signaling pathway, remains unclear. This study aimed to investigate the effect of the IRE1–XBP1 pathway on skeletal muscle differentiation. In C2C12 cells, knockdown of IRE1 and XBP1 in cells remarkably suppressed differentiation. In addition, apoptosis and autophagy were dramatically enhanced in the XBP1-knockdown cells, highlighting the participation of IRE1–XBP1 in cell survival maintenance with differentiation stimuli during skeletal muscle differentiation. In myogenic cells, we demonstrated that the expression of CDK5 (cyclin-dependent kinase 5) is regulated by XBP1s, and we propose that XBP1 regulates the expression of MyoD family genes via the induction of CDK5. In conclusion, this study revealed that IRE1–XBP1 signaling plays critical roles in cell viability and the expression of differentiation-related genes in predifferentiated myoblasts and during the early differentiation phase.

scholarly journals The steroid receptor coactivator, GRIP-1, is necessary for MEF-2C-dependent gene expression and skeletal muscle differentiation

2000 ◽  
Vol 14 (10) ◽  
pp. 1209-1228 ◽  
Author(s):  
Shen Liang Chen ◽  
Dennis H. Dowhan ◽  
Brett M. Hosking ◽  
George E.O. Muscat
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Ectopic Expression ◽  
Steroid Receptor ◽  
Muscle Differentiation ◽  
C2c12 Cells ◽  
Bhlh Protein ◽  
Specific Gene ◽  
Skeletal Muscle Differentiation ◽  
Amino Terminal

Nuclear receptor-mediated activation of transcription involves coactivation by cofactors collectively denoted the steroid receptor coactivators (SRCs). The process also involves the subsequent recruitment of p300/CBP and PCAF to a complex that synergistically regulates transcription and remodels the chromatin. PCAF and p300 have also been demonstrated to function as critical coactivators for the muscle-specific basic helix–loop–helix (bHLH) protein MyoD during myogenic commitment. Skeletal muscle differentiation and the activation of muscle-specific gene expression is dependent on the concerted action of another bHLH factor, myogenin, and the MADS protein, MEF-2, which function in a cooperative manner. We examined the functional role of one SRC, GRIP-1, in muscle differentiation, an ideal paradigm for the analysis of the determinative events that govern the cell's decision to divide or differentiate. We observed that the mRNA encoding GRIP-1 is expressed in proliferating myoblasts and post-mitotic differentiated myotubes, and that protein levels increase during differentiation. Exogenous/ectopic expression studies with GRIP-1 sense and antisense vectors in myogenic C2C12 cells demonstrated that this SRC is necessary for (1) induction/activation of myogenin, MEF-2, and the crucial cell cycle regulator, p21, and (2) contractile protein expression and myotube formation. Furthermore, we demonstrate that the SRC GRIP-1 coactivates MEF-2C-mediated transcription. GRIP-1 also coactivates the synergistic transactivation of E box-dependent transcription by myogenin and MEF-2C. GST-pulldowns, mammalian two-hybrid analysis, and immunoprecipitation demonstrate that the mechanism involves direct interactions between MEF-2C and GRIP-1 and is associated with the ability of the SRC to interact with the MADS domain of MEF-2C. The HLH region of myogenin mediates the direct interaction of myogenin and GRIP-1. Interestingly, interaction with myogenic factors is mediated by two regions of GRIP-1, an amino-terminal bHLH–PAS region and the carboxy-terminal region between amino acids 1158 and 1423 (which encodes an activation domain, has HAT activity, and interacts with the coactivator-associated arginine methyltransferase). This work demonstrates that GRIP-1 potentiates skeletal muscle differentiation by acting as a critical coactivator for MEF-2C-mediated transactivation and is the first study to ascribe a function to the amino-terminal bHLH–PAS region of SRCs.

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