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 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 Muscle-specific overexpression of NCOATGK, splice variant of O-GlcNAcase, induces skeletal muscle atrophy

2011 ◽  
Vol 300 (3) ◽  
pp. C456-C465 ◽  
Author(s):  
Ping Huang ◽  
Shiuh-Rong Ho ◽  
Kai Wang ◽  
Bryan C. Roessler ◽  
Fengxue Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Development ◽  
Direct Evidence ◽  
Fluorescent Protein ◽  
Skeletal Muscle Atrophy ◽  
Skeletal Muscle Development ◽  
Muscle Creatine Kinase ◽  
Green Fluorescent ◽  
Spliced Variant

The protein O-linked β- N-acetylglucosamine ( O-GlcNAc) modification plays an important role in skeletal muscle development and physiological function. In this study, bitransgenic mice were generated that overexpressed NCOATGK, an O-GlcNAcase-inactive spliced variant of the O-GlcNAcase gene, specifically in skeletal muscle using the muscle creatine kinase promoter. Expression of the chimeric enhanced green fluorescent protein-NCOATGK transgene caused an increase of cellular O-GlcNAc levels, along with the accumulation and activation of proapoptotic factors in muscles of bitransgenic mice. The consequence of overexpressing the transgene for a 2-wk period was muscle atrophy and, in some cases, resulted in the death of male mice. Muscle atrophy is a common complication of many diseases, some of which correlate markedly with high cellular O-GlcNAc levels, such as diabetes. Our study provides direct evidence linking muscle atrophy and the disruption of O-GlcNAcase activity.

scholarly journals Study on the transcriptional regulatory mechanism of the MyoD1 gene in Guanling bovine

RSC Advances ◽  
2018 ◽  
Vol 8 (22) ◽  
pp. 12409-12419
Author(s):  
Di Zhou ◽  
Houqiang Xu ◽  
Wei Chen ◽  
Yuanyuan Wang ◽  
Ming Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Regulatory Mechanism ◽  
Early Stage ◽  
Myoblast Differentiation ◽  
Differentiation Process ◽  
Skeletal Muscle Development ◽  
Transcriptional Regulatory Mechanism ◽  
Transcriptional Regulatory

The MyoD1 gene plays a key role in regulating the myoblast differentiation process in the early stage of skeletal muscle development.

scholarly journals KLF5 regulates chicken skeletal muscle atrophy via the canonical Wnt/β-catenin signaling pathway

2020 ◽  
Vol 69 (4) ◽  
pp. 430-440
Author(s):  
Dong-Hao ZHANG ◽  
Hua-Dong YIN ◽  
Jing-Jing LI ◽  
Yan WANG ◽  
Chao-Wu YANG ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signaling Pathway ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Canonical Wnt ◽  
Chicken Skeletal Muscle

scholarly journals MicroRNA 322 Aggravates Dexamethasone-Induced Muscle Atrophy by Targeting IGF1R and INSR

2020 ◽  
Vol 21 (3) ◽  
pp. 1111 ◽  
Author(s):  
Hongwei Geng ◽  
Qinglong Song ◽  
Yunyun Cheng ◽  
Haoyang Li ◽  
Rui Yang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Immunosuppressive Agent ◽  
Skeletal Muscle Atrophy ◽  
Luciferase Reporter ◽  
C2c12 Myotubes ◽  
High Dose ◽  
Reporter Assays ◽  
Underlying Mechanisms

Dexamethasone (Dex) has been widely used as a potent anti-inflammatory, antishock, and immunosuppressive agent. However, high dose or long-term use of Dex is accompanied by side effects including skeletal muscle atrophy, whose underlying mechanisms remain incompletely understood. A number of microRNAs (miRNAs) have been shown to play key roles in skeletal muscle atrophy. Previous studies showed significantly increased miR-322 expression in Dex-treated C2C12 myotubes. In our study, the glucocorticoid receptor (GR) was required for Dex to increase miR-322 expression in C2C12 myotubes. miR-322 mimic or miR-322 inhibitor was used for regulating the expression of miR-322. Insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (INSR) were identified as target genes of miR-322 using luciferase reporter assays and played key roles in Dex-induced muscle atrophy. miR-322 overexpression promoted atrophy in Dex-treated C2C12 myotubes and the gastrocnemius muscles of mice. Conversely, miR-322 inhibition showed the opposite effects. These data suggested that miR-322 contributes to Dex-induced muscle atrophy via targeting of IGF1R and INSR. Furthermore, miR-322 might be a potential target to counter Dex-induced muscle atrophy. miR-322 inhibition might also represent a therapeutic approach for Dex-induced muscle atrophy.

scholarly journals Low Levels of Serum Tryptophan Underlie Skeletal Muscle Atrophy

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 978 ◽  
Author(s):  
Soranobu Ninomiya ◽  
Nobuhiko Nakamura ◽  
Hiroshi Nakamura ◽  
Taku Mizutani ◽  
Yuto Kaneda ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Skeletal Muscles ◽  
B Cell Lymphoma ◽  
Tryptophan Metabolism ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myoblast ◽  
Standard Diet ◽  
Deficient Diet ◽  
Low Levels

Sarcopenia is a poor prognosis factor in some cancer patients, but little is known about the mechanisms by which malignant tumors cause skeletal muscle atrophy. Tryptophan metabolism mediated by indoleamine 2,3-dioxygenase is one of the most important amino acid changes associated with cancer progression. Herein, we demonstrate the relationship between skeletal muscles and low levels of tryptophan. A positive correlation was observed between the volume of skeletal muscles and serum tryptophan levels in patients with diffuse large B-cell lymphoma. Low levels of tryptophan reduced C2C12 myoblast cell proliferation and differentiation. Fiber diameters in the tibialis anterior of C57BL/6 mice fed a tryptophan-deficient diet were smaller than those in mice fed a standard diet. Metabolomics analysis revealed that tryptophan-deficient diet downregulated glycolysis in the gastrocnemius and upregulated the concentrations of amino acids associated with the tricarboxylic acid cycle. The weights and muscle fiber diameters of mice fed the tryptophan-deficient diet recovered after switching to the standard diet. Our data showed a critical role for tryptophan in regulating skeletal muscle mass. Thus, the tryptophan metabolism pathway may be a promising target for preventing or treating skeletal muscle atrophies.

scholarly journals Overexpression of the Rybp Gene Inhibits Differentiation of Bovine Myoblasts into Myotubes

2018 ◽  
Vol 19 (7) ◽  
pp. 2082
Author(s):  
Xiaotong Su ◽  
Yanfang Zhao ◽  
Yaning Wang ◽  
Le Zhang ◽  
Linsen Zan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Molecular Breeding ◽  
Theoretical Foundation ◽  
Negative Control ◽  
Myoblast Differentiation ◽  
Rna Seq ◽  
Skeletal Muscle Development ◽  
Morphological Differences ◽  
Bovine Skeletal Muscle

RING1 and YY1 binding protein (Rybp) genes inhibit myogenesis in mice, but there are no reports on the effects of these genes in cattle. The aim of this study is to investigate the roles of the Rybp gene on bovine skeletal muscle development and myoblast differentiation. In the present study, the Rybp gene was overexpressed in bovine myoblasts via adenovirus. RNA-seq was performed to screen differentially expressed genes (DEGs). The results showed that overexpressing the Rybp gene inhibits the formation of myotubes. The morphological differences in myoblasts began on the second day and were very significant 6 days after adenovirus induction. A total of 1311 (707 upregulated and 604 downregulated) DEGs were screened using RNA-seq between myoblasts with added negative control adenoviruses (AD-NC) and Rybp adenoviruses (AD-Rybp) after 6 days of induction. Gene ontology (GO) and KEGG analysis revealed that the downregulated DEGs were mainly involved in biological functions related to muscle, and, of the 32 pathways, those associated with muscle development were significantly enriched for the identified DEGs. This study can not only provide a theoretical basis for the regulation of skeletal muscle development in cattle by exploring the roles of the Rybp gene in myoblast differentiation, but it can also lay a theoretical foundation for molecular breeding of beef cattle.

Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size

2009 ◽  
Vol 296 (6) ◽  
pp. C1258-C1270 ◽  
Author(s):  
Anne Ulrike Trendelenburg ◽  
Angelika Meyer ◽  
Daisy Rohner ◽  
Joseph Boyle ◽  
Shinji Hatakeyama ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Transforming Growth Factor ◽  
Negative Regulator ◽  
Bone Morphogenetic Protein 2 ◽  
Muscle Size ◽  
Skeletal Muscle Atrophy ◽  
Myoblast Differentiation ◽  
Activin Receptor

Myostatin is a negative regulator of skeletal muscle size, previously shown to inhibit muscle cell differentiation. Myostatin requires both Smad2 and Smad3 downstream of the activin receptor II (ActRII)/activin receptor-like kinase (ALK) receptor complex. Other transforming growth factor-β (TGF-β)-like molecules can also block differentiation, including TGF-β1, growth differentiation factor 11 (GDF-11), activins, bone morphogenetic protein 2 (BMP-2) and BMP-7. Myostatin inhibits activation of the Akt/mammalian target of rapamycin (mTOR)/p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes. Blockade of the Akt/mTOR pathway, using small interfering RNA to regulatory-associated protein of mTOR (RAPTOR), a component of TOR signaling complex 1 (TORC1), increases myostatin-induced phosphorylation of Smad2, establishing a myostatin signaling-amplification role for blockade of Akt. Blockade of RAPTOR also facilitates myostatin's inhibition of muscle differentiation. Inhibition of TORC2, via rapamycin-insensitive companion of mTOR (RICTOR), is sufficient to inhibit differentiation on its own. Furthermore, myostatin decreases the diameter of postdifferentiated myotubes. However, rather than causing upregulation of the E3 ubiquitin ligases muscle RING-finger 1 ( MuRF1) and muscle atrophy F-box ( MAFbx), previously shown to mediate skeletal muscle atrophy, myostatin decreases expression of these atrophy markers in differentiated myotubes, as well as other genes normally upregulated during differentiation. These findings demonstrate that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct “atrophy program.” In vivo, inhibition of myostatin increases muscle creatine kinase activity, coincident with an increase in muscle size, demonstrating that this in vitro differentiation measure is also upregulated in vivo.

scholarly journals Transcriptome-wide N6-Methyladenosine Methylome Profiling Reveals m6A Regulation of Skeletal Myoblast Differentiation in Cattle (Bos taurus)

2021 ◽  
Vol 9 ◽  
Author(s):  
Xinran Yang ◽  
Jianfang Wang ◽  
Xinhao Ma ◽  
Jiawei Du ◽  
Chugang Mei ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Bos Taurus ◽  
Myoblast Differentiation ◽  
Potential Candidate ◽  
Mammalian Skeletal Muscle ◽  
Mrna Levels ◽  
Skeletal Myogenesis ◽  
Skeletal Muscle Development ◽  
Differentially Methylated Genes

N6-methyladenosine (m6A) is the most prevalent methylation modification of eukaryotic mRNA, and it plays an important role in regulating gene expression. Previous studies have found that m6A methylation plays a role in mammalian skeletal muscle development. However, the effect of m6A on bovine skeletal myogenesis are still unclear. Here, we selected proliferating myoblasts (GM) and differentiated myotubes (on the 4th day of differentiation, DM) for m6A-seq and RNA-seq to explore the m6A methylation modification pattern during bovine skeletal myogenesis. m6A-seq analysis revealed that m6A methylation was an abundant modification of the mRNA in bovine myoblasts and myotubes. We scanned 5,691–8,094 m6A-modified transcripts, including 1,437 differentially methylated genes (DMGs). GO and KEGG analyses revealed that DMGs were primarily involved in transcriptional regulation and RNA metabolism, as well as insulin resistance and metabolic pathways related to muscle development. The combined analysis further identified 268 genes that had significant changes at both m6A and mRNA levels, suggesting that m6A modification may regulate myoblast differentiation by mediating the expression of these genes. Furthermore, we experimentally confirmed four genes related to myogenesis, including MYOZ2, TWIST1, KLF5 and MYOD1, with differential changes in both m6A and mRNA levels during bovine myoblast differentiation, indicating that they can be potential candidate targets for m6A regulation of skeletal myogenesis. Our results may provide new insight into molecular genetics and breeding of beef cattle, and provide a reference for investigating the mechanism of m6A regulating skeletal muscle development.

scholarly journals Longitudinal epi-transcriptome profiling reveals the crucial role of m6A in prenatal skeletal muscle development of pigs

2019 ◽  
Author(s):  
Xinxin Zhang ◽  
Yilong Yao ◽  
Jinghua Han ◽  
Yalan Yang ◽  
Yun Chen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Transcriptome Profiling ◽  
Rna Modification ◽  
C2c12 Myoblast ◽  
Skeletal Muscle Development ◽  
The Status ◽  
The Stability ◽  
Myoblast Cells ◽  
And Function

AbstractBackgroundN6-methyladenosine (m6A) is the most abundant RNA modification and essentially participates in the regulation of skeletal muscle development. However, the status and function of m6A methylation in prenatal myogenesis remains unclear now.ResultsIn our present study, we first demonstrate that chemical suppression of m6A and knockdown METTL14 significantly inhibit the differentiation and promote the proliferation of C2C12 myoblast cells. The mRNA expression of m6A reader protein IGF2BP1, which functions to promote the stability of target mRNA, continually decreases during the prenatal skeletal muscle development. Thereafter, profiling transcriptome-wide m6A for six developmental stage of prenatal skeletal muscle, which spanning two important waves of pig myogenesis, were performed using a refined MeRIP sequencing technology that is optimal for small-amount of RNA samples. Highly dynamic m6A methylomes across different development stages were then revealed, with majority of the affected genes enriched in pathways of skeletal muscle development. In association with the transcriptome-wide alterations, transcriptional regulatory factors (MyoD) and differentiated markers (MyHC, MYH1) of muscle development are simultaneously regulated with m6A and IGF2BP1. Knockdown of IGF2BP1 also suppresses myotube formation and promotes cell proliferation.ConclusionsThe present study clarifies the dynamics of RNA m6A methylation in the regulation of prenatal skeletal muscle development, providing a data baseline for future developmental as well as biomedical studies of m6A functions in muscle development and disease.

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