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 Enhanced expression of mouse c-ski accompanies terminal skeletal muscle differentiation in vivo and in vitro

1995 ◽  
Vol 204 (3) ◽  
pp. 291-300 ◽  
Author(s):  
Stephanie Namciu ◽  
Gary E. Lyons ◽  
Bruce K. Micales ◽  
Hong-Chen Heyman ◽  
Clemencia Colmenares ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Enhanced Expression

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 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 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 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.

Regulation of skeletal muscle differentiation in fibroblasts by exogenous MyoD gene in vitro and in vivo

2007 ◽  
Vol 302 (1-2) ◽  
pp. 233-239 ◽  
Author(s):  
Rui-feng Qin ◽  
Tian-qiu Mao ◽  
Xiao-ming Gu ◽  
Kai-jing Hu ◽  
Yan-pu Liu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Myod Gene

scholarly journals SWELL1-LRRC8 complex regulates skeletal muscle cell size, intracellular signalling, adiposity and glucose metabolism

2020 ◽  
Author(s):  
Ashutosh Kumar ◽  
Litao Xie ◽  
Chau My Ta ◽  
Antentor J. Hinton ◽  
Susheel K. Gunasekar ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ex Vivo ◽  
Anion Channel ◽  
Muscle Differentiation ◽  
Mtor Signaling ◽  
Skeletal Muscle Differentiation ◽  
Skeletal Myofiber ◽  
Cellular Oxygen

AbstractMaintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism, however the molecular mechanosensor remains unknown. Here, we show that SWELL1 (LRRC8a) functionally encodes a swell-activated anion channel that regulates PI3K-AKT, ERK1/2, mTOR signaling, muscle differentiation, myoblast fusion, cellular oxygen consumption, and glycolysis in skeletal muscle cells. SWELL1 over-expression in SWELL1 KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle targeted SWELL1 KO mice have smaller myofibers, generate less force ex vivo, and exhibit reduced exercise endurance, associated with increased adiposity under basal conditions, and glucose intolerance and insulin resistance when raised on a high-fat diet, compared to WT mice. These results reveal that the SWELL1-LRRC8 complex regulates insulin-PI3K-AKT-mTOR signalling in skeletal muscle to influence skeletal muscle differentiation in vitro and skeletal myofiber size, muscle function, adiposity and systemic metabolism in vivo.

scholarly journals SWELL1 regulates skeletal muscle cell size, intracellular signaling, adiposity and glucose metabolism

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ashutosh Kumar ◽  
Litao Xie ◽  
Chau My Ta ◽  
Antentor O Hinton ◽  
Susheel K Gunasekar ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Intracellular Signaling ◽  
Ex Vivo ◽  
Anion Channel ◽  
Muscle Differentiation ◽  
Mtor Signaling ◽  
Skeletal Muscle Differentiation ◽  
Skeletal Myofiber

Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism; however, the molecular mechanosensor remains unknown. Here, we show that SWELL1 (Lrrc8a) functionally encodes a swell-activated anion channel that regulates PI3K-AKT, ERK1/2, mTOR signaling, muscle differentiation, myoblast fusion, cellular oxygen consumption, and glycolysis in skeletal muscle cells. LRRC8A over-expression in Lrrc8a KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle-targeted Lrrc8a KO mice have smaller myofibers, generate less force ex vivo, and exhibit reduced exercise endurance, associated with increased adiposity under basal conditions, and glucose intolerance and insulin resistance when raised on a high-fat diet, compared to wild-type (WT) mice. These results reveal that the LRRC8 complex regulates insulin-PI3K-AKT-mTOR signaling in skeletal muscle to influence skeletal muscle differentiation in vitro and skeletal myofiber size, muscle function, adiposity and systemic metabolism in vivo.

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

2019 ◽  
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.

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