Myostatin: a modulator of skeletal-muscle stem cells

2005 ◽  
Vol 33 (6) ◽  
pp. 1513-1517 ◽  
Author(s):  
F.S. Walsh ◽  
A.J. Celeste
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Muscle Development ◽  
Transforming Growth Factor ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Mdx Mouse ◽  
Specific Expression ◽  
Myostatin Gene

Myostatin, or GDF-8 (growth and differentiation factor-8), was first identified through sequence identity with members of the BMP (bone morphogenetic protein)/TGF-β (transforming growth factor-β) superfamily. The skeletal-muscle-specific expression pattern of myostatin suggested a role in muscle development. Mice with a targeted deletion of the myostatin gene exhibit a hypermuscular phenotype. In addition, inactivating mutations in the myostatin gene have been identified in ‘double muscled’ cattle breeds, such as the Belgian Blue and Piedmontese, as well as in a hypermuscular child. These findings define myostatin as a negative regulator of skeletal-muscle development. Myostatin binds with high affinity to the receptor serine threonine kinase ActRIIB (activin type IIB receptor), which initiates signalling through a smad2/3-dependent pathway. In an effort to validate myostatin as a therapeutic target in a post-embryonic setting, a neutralizing antibody was developed by screening for inhibition of myostatin binding to ActRIIB. Administration of this antimyostatin antibody to adult mice resulted in a significant increase in both muscle mass and functional strength. Importantly, similar results were obtained in a murine model of muscular dystrophy, the mdx mouse. Unlike the myostatin-deficient animals, which exhibit both muscle hypertrophy and hyperplasia, the antibody-treated mice demonstrate increased musculature through a hypertrophic mechanism. These results validate myostatin inhibition as a therapeutic approach to muscle wasting diseases such as muscular dystrophy, sarcopenic frailty of the elderly and amylotrophic lateral sclerosis.

Myostatin-induced inhibition of the long noncoding RNA Malat1 is associated with decreased myogenesis

2013 ◽  
Vol 304 (10) ◽  
pp. C995-C1001 ◽  
Author(s):  
Rani Watts ◽  
Virginia L. Johnsen ◽  
Jane Shearer ◽  
Dustin S. Hittel
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Cell Growth ◽  
Noncoding Rna ◽  
Transforming Growth Factor ◽  
Day Treatment ◽  
Global Gene Expression ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Human Skeletal Muscle Cells

Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily of secreted proteins, is a potent negative regulator of myogenesis. Free myostatin induces the phosphorylation of the Smad family of transcription factors, which, in turn, regulates gene expression, via the canonical TGF-β signaling pathway. There is, however, emerging evidence that myostatin can regulate gene expression independent of Smad signaling. As such, we acquired global gene expression data from the gastrocnemius muscle of C57BL/6 mice following a 6-day treatment with recombinant myostatin compared with vehicle-treated animals. Of the many differentially expressed genes, the myostatin-associated decrease (−11.20-fold; P < 0.05) in the noncoding metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was the most significant and the most intriguing because of numerous reports describing its novel role in regulating cell growth. We therefore sought to further characterize the role of Malat1 expression in skeletal muscle myogenesis. RT-PCR-based quantification of C2C12 and primary human skeletal muscle cells revealed a significant and persistent upregulation (4- to 7-fold; P < 0.05) of Malat1 mRNA during the differentiation of myoblasts into myotubes. Conversely, targeted knockdown of Malat1 using siRNA suppressed myoblast proliferation by arresting cell growth in the G0/G1phase. These results reveal Malat1 as novel downstream target of myostatin with a considerable ability to regulate myogenesis. The identification of new targets of myostatin will have important repercussions for regenerative biology through inhibition and/or reversal of muscle atrophy and wasting diseases.

Transforming growth factor-β and myostatin signaling in skeletal muscle

2008 ◽  
Vol 104 (3) ◽  
pp. 579-587 ◽  
Author(s):  
Helen D. Kollias ◽  
John C. McDermott
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Muscle Development ◽  
Cellular Proliferation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Related Family ◽  
Cytokine Milieu

The superfamily of transforming growth factor-β (TGF-β) cytokines has been shown to have profound effects on cellular proliferation, differentiation, and growth. Recently, there have been major advances in our understanding of the signaling pathway(s) conveying TGF-β signals to the nucleus to ultimately control gene expression. One tissue that is potently influenced by TGF-β superfamily signaling is skeletal muscle. Skeletal muscle ontogeny and postnatal physiology have proven to be exquisitely sensitive to the TGF-β superfamily cytokine milieu in various animal systems from mice to humans. Recently, major strides have been made in understanding the role of TGF-β and its closely related family member, myostatin, in these processes. In this overview, we will review recent advances in our understanding of the TGF-β and myostatin signaling pathways and, in particular, focus on the implications of this signaling pathway for skeletal muscle development, physiology, and pathology.

scholarly journals Enhanced Muscle Growth by Plasmid-Mediated Delivery of Myostatin Propeptide

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Shengwei Hu ◽  
Chuangfu Chen ◽  
Jingliang Sheng ◽  
Yufang Sun ◽  
Xudong Cao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transforming Growth Factor Beta ◽  
Muscle Development ◽  
Transforming Growth Factor ◽  
Genetic Manipulation ◽  
Muscle Growth ◽  
Negative Regulator ◽  
Dna Encoding ◽  
Single Intramuscular Injection ◽  
Myostatin Inhibition

Myostatin is a member of the transforming growth factor beta (TGF-β) superfamily that functions as a negative regulator of skeletal muscle development and growth. Myostatin blockade therefore offers a strategy for promoting muscle growth in livestock production without resorting to genetic manipulation. In this report, we examined the effect of myostatin inhibition by plasmid-mediated delivery of a mutant myostatin propeptide (MProD76A), a natural inhibitor of myostatin, on the growth performance of mice. A significant increase in skeletal muscle mass was observed after a single intramuscular injection of naked plasmid DNA encoding MProD76A into mice. Enhanced muscle growth occurred because of myofiber hypertrophy, but no cardiac muscle hypertrophy and organomegaly was observed in the mice after myostatin inhibition by plasmid-mediated MProD76A delivery. These results demonstrate a promising approach to enhancing muscle growth that warrants further investigation in domestic animals.

scholarly journals Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1506
Author(s):  
Aqsa Iqbal ◽  
Ulrike May ◽  
Stuart N. Prince ◽  
Tero A.H. Järvinen ◽  
Ahlke Heydemann
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscular Dystrophy ◽  
Muscle Damage ◽  
Targeted Delivery ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Skeletal Muscle Function ◽  
Skeletal Muscle Damage ◽  
Homing Peptide

Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFβ1 has proven beneficial in mouse models of muscular dystrophy, but the global strategies of TGFβ1 inhibition produce significant detrimental side effects. Here, we investigated whether murine muscular dystrophy lesion-specific inhibition of TGFβ1 signaling by the targeted delivery of therapeutic decorin (a natural TGFβ inhibitor) by a vascular homing peptide CAR (CARSKNKDC) would reduce skeletal muscle fibrosis and pathology and increase functional characteristics of skeletal muscle. We demonstrate that CAR peptide homes to dystrophic lesions with specificity in two muscular dystrophy models. Recombinant fusion protein consisting of CAR peptide and decorin homes selectively to sites of skeletal muscle damage in mdxDBA2/J and gamma-sarcoglycan deficient DBA2/J mice. This targeted delivery reduced TGFβ1 signaling as demonstrated by reduced nuclear pSMAD staining. Three weeks of targeted decorin treatment decreased both membrane permeability and fibrosis and improved skeletal muscle function in comparison to control treatments in the mdxD2 mice. These results show that selective delivery of decorin to the sites of skeletal muscle damage attenuates the progression of murine muscular dystrophy.

scholarly journals Fibromodulin Modulates Chicken Skeletal Muscle Development via the Transforming Growth Factor-β Signaling Pathway

Animals ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1477
Author(s):  
Huadong Yin ◽  
Can Cui ◽  
Shunshun Han ◽  
Yuqi Chen ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Matrix Protein ◽  
Muscle Development ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Skeletal Muscle Development

Fibromodulin (Fmod), which is an extracellular matrix protein, belongs to the extracellular matrix small-leucine-rich proteoglycan family. Fmod is abundantly expressed in muscles and connective tissues and is involved in biological regulation processes, including cell apoptosis, cell adhesion, and modulation of cytokine activity. Fmod is the main regulator of myostatin, which controls the development of muscle cells, but its regulatory path is unknown. Chicken models are ideal for studying embryonic skeletal muscle development; therefore, to investigate the mechanism of Fmod in muscle development, Fmod-silenced and Fmod-overexpressed chicken myoblasts were constructed. The results showed that Fmod plays a positive role in differentiation by detecting the expression of myogenic differentiation markers, immunofluorescence of MyHC protein, and myotube formation in myoblasts. Fmod regulates expression of atrophy-related genes to alleviate muscle atrophy, which was confirmed by histological analysis of breast muscles in Fmod-modulated chicks in vivo. Additionally, genes differentially expressed between Fmod knockdown and normal myoblasts were enriched in the signaling pathway of transforming growth factor β (TGF-β). Both Fmod-silenced and Fmod-overexpressed myoblasts regulated the expression of TGFBR1 and p-Smad3. Thus, Fmod can promote differentiation but not proliferation of myoblasts by regulating the TGF-β signaling pathway, which may serve a function in muscular atrophy.

scholarly journals Regulation of Myostatin on the Growth and Development of Skeletal Muscle

2021 ◽  
Vol 9 ◽  
Author(s):  
Ming-Ming Chen ◽  
Yi-Ping Zhao ◽  
Yue Zhao ◽  
Shou-Long Deng ◽  
Kun Yu
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Growth And Development ◽  
Transforming Growth Factor ◽  
Muscle Protein ◽  
Myogenic Differentiation ◽  
Reactive Oxygen Species Generation ◽  
Transforming Growth Factor Β ◽  
Muscle Quality ◽  
Myostatin Gene

Myostatin (MSTN), a member of the transforming growth factor-β superfamily, can negatively regulate the growth and development of skeletal muscle by autocrine or paracrine signaling. Mutation of the myostatin gene under artificial or natural conditions can lead to a significant increase in muscle quality and produce a double-muscle phenotype. Here, we review the similarities and differences between myostatin and other members of the transforming growth factor-β superfamily and the mechanisms of myostatin self-regulation. In addition, we focus extensively on the regulation of myostatin functions involved in myogenic differentiation, myofiber type conversion, and skeletal muscle protein synthesis and degradation. Also, we summarize the induction of reactive oxygen species generation and oxidative stress by myostatin in skeletal muscle. This review of recent insights into the function of myostatin will provide reference information for future studies of myostatin-regulated skeletal muscle formation and may have relevance to agricultural fields of study.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals Amelioration of Muscular Dystrophy by Transgenic Expression of Niemann-Pick C1

2009 ◽  
Vol 20 (1) ◽  
pp. 146-152 ◽  
Author(s):  
Michelle S. Steen ◽  
Marvin E. Adams ◽  
Yan Tesch ◽  
Stanley C. Froehner
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Mdx Mouse ◽  
Lysosomal Storage ◽  
Transgenic Expression ◽  
New Therapeutic Approaches ◽  
Human Disorders ◽  
Niemann Pick ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking α-dystrobrevin (Dtna−/−), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna−/− mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.

Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin

2003 ◽  
Vol 285 (4) ◽  
pp. E876-E888 ◽  
Author(s):  
Suzanne Reisz-Porszasz ◽  
Shalender Bhasin ◽  
Jorge N. Artaza ◽  
Ruoqing Shen ◽  
Indrani Sinha-Hikim ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Fluorescent Protein ◽  
Male Mice ◽  
Wild Type ◽  
Specific Expression ◽  
Muscle Weight ◽  
Myostatin Gene

Mutations in the myostatin gene are associated with hypermuscularity, suggesting that myostatin inhibits skeletal muscle growth. We postulated that increased tissue-specific expression of myostatin protein in skeletal muscle would induce muscle loss. To investigate this hypothesis, we generated transgenic mice that overexpress myostatin protein selectively in the skeletal muscle, with or without ancillary expression in the heart, utilizing cDNA constructs in which a wild-type (MCK/Mst) or mutated muscle creatine kinase (MCK-3E/Mst) promoter was placed upstream of mouse myostatin cDNA. Transgenic mice harboring these MCK promoters linked to enhanced green fluorescent protein (EGFP) expressed the reporter protein only in skeletal and cardiac muscles (MCK) or in skeletal muscle alone (MCK-3E). Seven-week-old animals were genotyped by PCR of tail DNA or by Southern blot analysis of liver DNA. Myostatin mRNA and protein, measured by RT-PCR and Western blot, respectively, were significantly higher in gastrocnemius, quadriceps, and tibialis anterior of MCK/Mst-transgenic mice compared with wild-type mice. Male MCK/Mst-transgenic mice had 18–24% lower hind- and forelimb muscle weight and 18% reduction in quadriceps and gastrocnemius fiber cross-sectional area and myonuclear number (immunohistochemistry) than wild-type male mice. Male transgenic mice with mutated MCK-3E promoter showed similar effects on muscle mass. However, female transgenic mice with either type of MCK promoter did not differ from wild-type controls in either body weight or skeletal muscle mass. In conclusion, increased expression of myostatin in skeletal muscle is associated with lower muscle mass and decreased fiber size and myonuclear number, decreased cardiac muscle mass, and increased fat mass in male mice, consistent with its role as an inhibitor of skeletal muscle mass. The mechanism of gender specificity remains to be clarified.

Effect of kinin B2 receptor ablation on skeletal muscle development and myostatin gene expression

Neuropeptides ◽  
2010 ◽  
Vol 44 (2) ◽  
pp. 209-214 ◽  
Author(s):  
K. de Picoli Souza ◽  
E.C. Batista ◽  
E.D. Silva ◽  
F.C. Reis ◽  
S.M.A. Silva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Muscle Development ◽  
Skeletal Muscle Development ◽  
Myostatin Gene
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