scholarly journals JAK1–STAT1–STAT3, a key pathway promoting proliferation and preventing premature differentiation of myoblasts

2007 ◽  
Vol 179 (1) ◽  
pp. 129-138 ◽  
Author(s):  
Luguo Sun ◽  
Kewei Ma ◽  
Haixia Wang ◽  
Fang Xiao ◽  
Yan Gao ◽  
...  
Keyword(s):  
Myogenic Differentiation ◽  
Muscle Growth ◽  
Janus Kinase ◽  
Myoblast Differentiation ◽  
Muscle Stem Cell ◽  
Janus Kinase 1 ◽  
Binding Factor ◽  
Proliferation And Differentiation ◽  
Myoblast Proliferation ◽  
Concomitant Reduction

Skeletal muscle stem cell–derived myoblasts are mainly responsible for postnatal muscle growth and injury-induced muscle regeneration. However, the cellular signaling pathways controlling the proliferation and differentiation of myoblasts are not fully understood. We demonstrate that Janus kinase 1 (JAK1) is required for myoblast proliferation and that it also functions as a checkpoint to prevent myoblasts from premature differentiation. Deliberate knockdown of JAK1 in both primary and immortalized myoblasts induces precocious myogenic differentiation with a concomitant reduction in cell proliferation. This is caused, in part, by an accelerated induction of MyoD, myocyte enhancer–binding factor 2 (MEF2), p21Cip1, and p27Kip1, a faster down-regulation of Id1, and an increase in MEF2-dependent gene transcription. Downstream of JAK1, of all the signal transducer and activator of transcriptions (STATs) present in myoblasts, we find that only STAT1 knockdown promotes myogenic differentiation in both primary and immortalized myoblasts. Leukemia inhibitory factor stimulates myoblast proliferation and represses differentiation via JAK1–STAT1–STAT3. Thus, JAK1–STAT1–STAT3 constitutes a signaling pathway that promotes myoblast proliferation and prevents premature myoblast differentiation.

scholarly journals MicroRNA-27b-3p Targets the Myostatin Gene to Regulate Myoblast Proliferation and Is Involved in Myoblast Differentiation

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 423
Author(s):  
Genxi Zhang ◽  
Mingliang He ◽  
Pengfei Wu ◽  
Xinchao Zhang ◽  
Kaizhi Zhou ◽  
...  
Keyword(s):  
Muscle Growth ◽  
Luciferase Reporter ◽  
Myoblast Differentiation ◽  
Regulation Mechanism ◽  
Rna Seq ◽  
Myostatin Gene ◽  
Primary Myoblasts ◽  
Chicken Muscle ◽  
Proliferation And Differentiation ◽  
Myoblast Proliferation

microRNAs play an important role in the growth and development of chicken embryos, including the regulation of skeletal muscle genesis, myoblast proliferation, differentiation, and apoptosis. Our previous RNA-seq studies showed that microRNA-27b-3p (miR-27b-3p) might play an important role in regulating the proliferation and differentiation of chicken primary myoblasts (CPMs). However, the mechanism of miR-27b-3p regulating the proliferation and differentiation of CPMs is still unclear. In this study, the results showed that miR-27b-3p significantly promoted the proliferation of CPMs and inhibited the differentiation of CPMs. Then, myostatin (MSTN) was confirmed to be the target gene of miR-27b-3p by double luciferase reporter assay, RT-qPCR, and Western blot. By overexpressing and interfering with MSTN expression in CPMs, the results showed that overexpression of MSTN significantly inhibited the proliferation and differentiation of CPMs. In contrast, interference of MSTN expression had the opposite effect. This study showed that miR-27b-3p could promote the proliferation of CPMs by targeting MSTN. Interestingly, both miR-27b-3p and MSTN can inhibit the differentiation of CPMs. These results provide a theoretical basis for further understanding the function of miR-27b-3p in chicken and revealing its regulation mechanism on chicken muscle growth.

scholarly journals 2-D08 treatment regulates C2C12 myoblast proliferation and differentiation via the Erk1/2 and proteasome signaling pathways

2021 ◽  
Author(s):  
Hyunju Liu ◽  
Su-Mi Lee ◽  
Hosouk Joung
Keyword(s):  
Myogenic Differentiation ◽  
C2c12 Cell ◽  
C2c12 Cells ◽  
Covalent Attachment ◽  
Myoblast Differentiation ◽  
C2c12 Myoblast ◽  
Long Term Effects ◽  
Proliferation And Differentiation ◽  
Myoblast Proliferation ◽  
Myoblast Cells

AbstractSUMOylation is one of the post-translational modifications that involves the covalent attachment of the small ubiquitin-like modifier (SUMO) to the substrate. SUMOylation regulates multiple biological processes, including myoblast proliferation, differentiation, and apoptosis. 2-D08 is a synthetically available flavone, which acts as a potent cell-permeable SUMOylation inhibitor. Its mechanism of action involves preventing the transfer of SUMO from the E2 thioester to the substrate without influencing SUMO-activating enzyme E1 (SAE-1/2) or E2 Ubc9-SUMO thioester formation. However, both the effects and mechanisms of 2-D08 on C2C12 myoblast cells remain unclear. In the present study, we found that treatment with 2-D08 inhibits C2C12 cell proliferation and differentiation. We confirmed that 2-D08 significantly hampers the viability of C2C12 cells. Additionally, it inhibited myogenic differentiation, decreasing myosin heavy chain (MHC), MyoD, and myogenin expression. Furthermore, we confirmed that 2-D08-mediated anti-myogenic effects impair myoblast differentiation and myotube formation, reducing the number of MHC-positive C2C12 cells. In addition, we found that 2-D08 induces the activation of ErK1/2 and the degradation of MyoD and myogenin in C2C12 cells. Taken together, these results indicated that 2-D08 treatment results in the deregulated proliferation and differentiation of myoblasts. However, further research is needed to investigate the long-term effects of 2-D08 on skeletal muscles.

Anemic Hypoxemia Reduces Myoblast Proliferation and Muscle Growth in Late Gestation Fetal Sheep

2021 ◽  
Author(s):  
Paul J. Rozance ◽  
Stephanie R Wesolowski ◽  
Sonnet S. Jonker ◽  
Laura D Brown
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Muscle Growth ◽  
Late Gestation ◽  
Whole Body ◽  
Myoblast Differentiation ◽  
Fetal Sheep ◽  
Body Protein ◽  
Skeletal Muscle Growth ◽  
Myoblast Proliferation

Fetal skeletal muscle growth requires myoblast proliferation, differentiation, and fusion into myofibers in addition to protein accretion for fiber hypertrophy. Oxygen is an important regulator of this process. Therefore, we hypothesized that fetal anemic hypoxemia would inhibit skeletal muscle growth. Studies were performed in late gestation fetal sheep that were bled to anemic, and therefore hypoxemic, conditions beginning at ~125 days of gestation (term = 148 days) for 9 ± 0 days (n=19) and compared to control fetuses (n=16). A metabolic study was performed on gestational day ~134 to measure fetal protein kinetic rates. Myoblast proliferation and myofiber area were determined in biceps femoris (BF), tibialis anterior (TA), and flexor digitorum superficialis (FDS) muscles. mRNA expression of muscle regulatory factors was determined in BF. Fetal arterial hematocrit and oxygen content were 28% and 52% lower, respectively, in anemic fetuses. Fetal weight and whole-body protein synthesis, breakdown, and accretion rates were not different between groups. Hindlimb length, however, was 7% shorter in anemic fetuses. TA and FDS muscles weighed less and FDS myofiber area was smaller in anemic fetuses compared to controls. The percentage of Pax7+ myoblasts that expressed Ki67 was lower in BF and tended to be lower in FDS from anemic fetuses indicating reduced myoblast proliferation. There was less MYOD and MYF6 mRNA expression in anemic vs. control BF consistent with reduced myoblast differentiation. These results indicate that fetal anemic hypoxemia reduced muscle growth. We speculate that fetal muscle growth may be improved by strategies that increase oxygen availability.

scholarly journals Loss of IGF-IEa or IGF-IEb Impairs Myogenic Differentiation

Endocrinology ◽  
2011 ◽  
Vol 152 (5) ◽  
pp. 1923-1934 ◽  
Author(s):  
Ronald W. Matheny ◽  
Bradley C. Nindl
Keyword(s):  
Splice Variants ◽  
Myogenic Differentiation ◽  
Horse Serum ◽  
Myoblast Differentiation ◽  
Proliferation And Differentiation ◽  
Igf I ◽  
Simultaneous Loss ◽  
Functional Relevance ◽  
Free Media ◽  
The Impact

Actions of protein products resulting from alternative splicing of the Igf1 gene have received increasing attention in recent years. However, the significance and functional relevance of these observations remain poorly defined. To address functions of IGF-I splice variants, we examined the impact of loss of IGF-IEa and IGF-IEb on the proliferation and differentiation of cultured mouse myoblasts. RNA interference-mediated reductions in total IGF-I, IGF-IEa alone, or IGF-IEb alone had no effect on cell viability in growth medium. However, cells deficient in total IGF-I or IGF-IEa alone proliferated significantly slower than control cells or cells deficient in IGF-IEb in serum-free media. Simultaneous loss of both or specific loss of either splice variant significantly inhibited myosin heavy chain (MyHC) immunoreactivity by 70–80% (P < 0.01) under differentiation conditions (48 h in 2% horse serum) as determined by Western immunoblotting. This loss in protein was associated with reduced MyHC isoform mRNAs, because reductions in total IGF-I or IGF-IEa mRNA significantly reduced MyHC mRNAs by approximately 50–75% (P < 0.05). Loss of IGF-IEb also reduced MyHC isoform mRNA significantly, with the exception of Myh7, but to a lesser degree (∼20–40%, P < 0.05). Provision of mature IGF-I, but not synthetic E peptides, restored Myh3 expression to control levels in cells deficient in IGF-IEa or IGF-IEb. Collectively, these data suggest that IGF-I splice variants may regulate myoblast differentiation through the actions of mature IGF-I and not the E peptides.

Myostatin is an inhibitor of myogenic differentiation

2002 ◽  
Vol 282 (5) ◽  
pp. C993-C999 ◽  
Author(s):  
Ramón Rı́os ◽  
Isabel Carneiro ◽  
Víctor M. Arce ◽  
Jesús Devesa
Keyword(s):  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Muscle Growth ◽  
Precursor Cell ◽  
Myoblast Differentiation ◽  
Mrna Levels ◽  
Downstream Target ◽  
Muscle Regulatory Factors ◽  
Muscle Precursor Cell ◽  
Autocrine Mechanism

Myostatin (MSTN), a transforming growth factor (TGF)-β superfamily member, has been shown to negatively regulate muscle growth by inhibiting muscle precursor cell proliferation. Here, we stably transfected C2C12 cells with mouse MSTN cDNA to investigate its possible role in myoblast differentiation. We found that MSTN cDNA overexpression reversibly inhibits the myogenic process by downregulating mRNA levels of the muscle regulatory factors myoD and myogenin, as well as the activity of their downstream target creatine kinase. Taking into consideration that MSTN expression during development is restricted to muscle, our results suggest that MSTN probably regulates myogenic differentiation by an autocrine mechanism.

scholarly journals Thyroid Hormone Receptor α Plays an Essential Role in Male Skeletal Muscle Myoblast Proliferation, Differentiation, and Response to Injury

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 4-15 ◽  
Author(s):  
Anna Milanesi ◽  
Jang-Won Lee ◽  
Nam-Ho Kim ◽  
Yan-Yun Liu ◽  
An Yang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Essential Role ◽  
Mutant Mouse ◽  
Thyroid Hormone Receptor ◽  
Myogenic Differentiation ◽  
Myoblast Differentiation ◽  
Primary Myoblasts ◽  
Myoblast Proliferation

Abstract Thyroid hormone plays an essential role in myogenesis, the process required for skeletal muscle development and repair, although the mechanisms have not been established. Skeletal muscle develops from the fusion of precursor myoblasts into myofibers. We have used the C2C12 skeletal muscle myoblast cell line, primary myoblasts, and mouse models of resistance to thyroid hormone (RTH) α and β, to determine the role of thyroid hormone in the regulation of myoblast differentiation. T3, which activates thyroid hormone receptor (TR) α and β, increased myoblast differentiation whereas GC1, a selective TRβ agonist, was minimally effective. Genetic approaches confirmed that TRα plays an important role in normal myoblast proliferation and differentiation and acts through the Wnt/β-catenin signaling pathway. Myoblasts with TRα knockdown, or derived from RTH-TRα PV (a frame-shift mutation) mice, displayed reduced proliferation and myogenic differentiation. Moreover, skeletal muscle from the TRα1PV mutant mouse had impaired in vivo regeneration after injury. RTH-TRβ PV mutant mouse model skeletal muscle and derived primary myoblasts did not have altered proliferation, myogenic differentiation, or response to injury when compared with control. In conclusion, TRα plays an essential role in myoblast homeostasis and provides a potential therapeutic target to enhance skeletal muscle regeneration.

scholarly journals Human myostatin negatively regulates human myoblast growth and differentiation

2011 ◽  
Vol 301 (1) ◽  
pp. C195-C203 ◽  
Author(s):  
Craig McFarlane ◽  
Gu Zi Hui ◽  
Wong Zhi Wei Amanda ◽  
Hiu Yeung Lau ◽  
Sudarsanareddy Lokireddy ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Muscle Growth ◽  
Notch Pathway ◽  
Transforming Growth Factor Β ◽  
Myoblast Differentiation ◽  
Myogenic Regulatory Factor ◽  
Human Myoblast

Myostatin, a member of the transforming growth factor-β superfamily, has been implicated in the potent negative regulation of myogenesis in murine models. However, little is known about the mechanism(s) through which human myostatin negatively regulates human skeletal muscle growth. Using human primary myoblasts and recombinant human myostatin protein, we show here that myostatin blocks human myoblast proliferation by regulating cell cycle progression through targeted upregulation of p21. We further show that myostatin regulates myogenic differentiation through the inhibition of key myogenic regulatory factors including MyoD, via canonical Smad signaling. In addition, we have for the first time demonstrated the capability of myostatin to regulate the Notch signaling pathway during inhibition of human myoblast differentiation. Treatment with myostatin results in the upregulation of Hes1, Hes5, and Hey1 expression during differentiation; moreover, when we interfere with Notch signaling, through treatment with the γ-secretase inhibitor L-685,458, we find enhanced myotube formation despite the presence of excess myostatin. Therefore, blockade of the Notch pathway relieves myostatin repression of differentiation, and myostatin upregulates Notch downstream target genes. Immunoprecipitation studies demonstrate that myostatin treatment of myoblasts results in enhanced association of Notch1-intracellular domain with Smad3, providing an additional mechanism through which myostatin targets and represses the activity of the myogenic regulatory factor MyoD. On the basis of these results, we suggest that myostatin function and mechanism of action are very well conserved between species, and that myostatin regulation of postnatal myogenesis involves interactions with numerous downstream signaling mediators, including the Notch pathway.

scholarly journals KDM4A regulates myogenesis by demethylating H3K9me3 of myogenic regulatory factors

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Qi Zhu ◽  
Feng Liang ◽  
Shufang Cai ◽  
Xiaorong Luo ◽  
Tianqi Duo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Proliferation ◽  
Satellite Cells ◽  
Muscle Development ◽  
Kinase Inhibitor ◽  
Myogenic Differentiation ◽  
Myoblast Differentiation ◽  
Proliferation And Differentiation ◽  
H3k9me3 Level

AbstractHistone lysine demethylase 4A (KDM4A) plays a crucial role in regulating cell proliferation, cell differentiation, development and tumorigenesis. However, little is known about the function of KDM4A in muscle development and regeneration. Here, we found that the conditional ablation of KDM4A in skeletal muscle caused impairment of embryonic and postnatal muscle formation. The loss of KDM4A in satellite cells led to defective muscle regeneration and blocked the proliferation and differentiation of satellite cells. Myogenic differentiation and myotube formation in KDM4A-deficient myoblasts were inhibited. Chromatin immunoprecipitation assay revealed that KDM4A promoted myogenesis by removing the histone methylation mark H3K9me3 at MyoD, MyoG and Myf5 locus. Furthermore, inactivation of KDM4A in myoblasts suppressed myoblast differentiation and accelerated H3K9me3 level. Knockdown of KDM4A in vitro reduced myoblast proliferation through enhancing the expression of the cyclin-dependent kinase inhibitor P21 and decreasing the expression of cell cycle regulator Cyclin D1. Together, our findings identify KDM4A as an important regulator for skeletal muscle development and regeneration, orchestrating myogenic cell proliferation and differentiation.

scholarly journals The Effects of Marine Algal Polyphenols, Phlorotannins, on Skeletal Muscle Growth in C2C12 Muscle Cells via Smad and IGF-1 Signaling Pathways

Marine Drugs ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. 266
Author(s):  
Seo-Young Kim ◽  
Ji-Hyeok Lee ◽  
Nalae Kang ◽  
Kil-Nam Kim ◽  
You-Jin Jeon
Keyword(s):  
Skeletal Muscle ◽  
Muscle Growth ◽  
Negative Regulator ◽  
Growth Effect ◽  
C2c12 Myoblast ◽  
Synthetic Drugs ◽  
Proliferation And Differentiation ◽  
Myoblast Proliferation ◽  
C2c12 Muscle Cells ◽  
Marine Algal

Skeletal muscle is an important tissue in energy metabolism and athletic performance. The use of effective synthetic supplements and drugs to promote muscle growth is limited by various side effects. Moreover, their use is prohibited by anti-doping agencies; hence, natural alternatives are needed. Therefore, we evaluated the muscle growth effect of substances that can act like synthetic supplements from edible marine algae. First, we isolated six marine algal polyphenols belonging to the phlorotannin class, namely dieckol (DK), 2,7′′-phloroglucinol-6,6′-bieckol (PHB), phlorofucofuroeckol A (PFFA), 6,6′-bieckol (6,6-BK), pyrogallol-phloroglucinol-6,6′-bieckol (PPB), and phloroglucinol (PG) from an edible brown alga, Ecklonia cava and evaluated their effects on C2C12 myoblasts proliferation and differentiation. Of the six phlorotannin isolates evaluated, DK and PHB induced the highest degree of C2C12 myoblast proliferation. In addition, DK and PHB regulates myogenesis by down-regulating the Smad signaling, a negative regulator, and up-regulating the insulin-like growth factor-1 (IGF-1) signaling, a positive regulator. Interestingly, DK and PHB bind strongly to myostatin, which is an inhibitor of myoblast proliferation, while also binding to IGF-1 receptors. Moreover, they bind to IGF-1 receptor. These results suggest that DK and PHB are potential natural muscle building supplements and could be a safer alternative to synthetic drugs.

Myogenic differentiation during regrowth of atrophied skeletal muscle is associated with inactivation of GSK-3β

2007 ◽  
Vol 292 (5) ◽  
pp. C1636-C1644 ◽  
Author(s):  
Jos L. J. van der Velden ◽  
Ramon C. J. Langen ◽  
Marco C. J. M. Kelders ◽  
Jodil Willems ◽  
Emiel F. M. Wouters ◽  
...  
Keyword(s):  
Muscle Atrophy ◽  
Glycogen Synthase ◽  
Myogenic Differentiation ◽  
Hindlimb Suspension ◽  
Akt Phosphorylation ◽  
Proliferation And Differentiation ◽  
Igf I ◽  
Myoblast Proliferation ◽  
Gsk 3Β ◽  
First Time

Muscle atrophy contributes to morbidity and mortality in aging and chronic disease, emphasizing the need to gain understanding of the mechanisms involved in muscle atrophy and (re)growth. We hypothesized that the magnitude of muscle regrowth during recovery from atrophy determines whether myonuclear accretion and myogenic differentiation are required and that insulin-like growth factor (IGF)-I/Akt/glycogen synthase kinase (GSK)-3β signaling differs between regrowth responses. To address this hypothesis we subjected mice to hindlimb suspension (HS) to induce atrophy of soleus (−40%) and plantaris (−27%) muscle. Reloading-induced muscle regrowth was complete after 14 days and involved an increase in IGF-IEa mRNA expression that coincided with Akt phosphorylation in both muscles. In contrast, phosphorylation and inactivation of GSK-3β were observed during soleus regrowth only. Furthermore, soleus but not plantaris regrowth involved muscle regeneration based on a transient increase in expression of histone 3.2 and myosin heavy chain-perinatal, which are markers of myoblast proliferation and differentiation, and a strong induction of muscle regulatory factor (MRF) expression. Experiments in cultured muscle cells showed that IGF-I-induced MRF expression is facilitated by inactivation of GSK-3β and selectively occurs in the myoblast population. This study suggests that induction of IGF-I expression and Akt phosphorylation during recovery from muscle atrophy is independent of the magnitude of muscle regrowth. Moreover, our data demonstrate for the first time that the regenerative response characterized by myoblast proliferation, differentiation, and increased MRF expression in recovering muscle is associated with the magnitude of regrowth and may be regulated by inactivation of GSK-3β.

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