scholarly journals Novel Myostatin-Specific Antibody Enhances Muscle Strength in Muscle Disease Models

2020 ◽  
Author(s):  
Hiroyasu Muramatsu ◽  
Taichi Kuramochi ◽  
Hitoshi Katada ◽  
Atsunori Ueyama ◽  
Yoshinao Ruike ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Transforming Growth Factor ◽  
Muscle Growth ◽  
Muscle Disease ◽  
Negative Regulator ◽  
Disease Models ◽  
Muscular Disorders ◽  
Disease Therapy ◽  
Improve Muscle Strength ◽  
Strength Improvement

Abstract Myostatin, a member of the transforming growth factor-b superfamily, is an attractive target for muscle disease therapy because of its role as a negative regulator of muscle growth and strength. Here, we describe a novel antibody therapeutic approach that maximizes the potential of myostatin-targeted therapy. We generated an antibody, GYM329, that specifically binds the latent form of myostatin and inhibits its activation. Additionally, via “sweeping antibody technology”, GYM329 reduces or “sweeps” myostatin in the muscle and plasma. Compared with conventional anti-myostatin agents, GYM329 and its surrogate antibody exhibit superior muscle strength-improvement effects in three different mouse disease models. We also demonstrate that the superior efficacy of GYM329 is due to its myostatin specificity and sweeping capability. Furthermore, we show that a GYM329 surrogate increases muscle mass in normal cynomolgus monkeys without any obvious toxicity. Our findings indicate the potential of GYM329 to improve muscle strength in patients with muscular disorders.

scholarly journals Novel myostatin-specific antibody enhances muscle strength in muscle disease models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroyasu Muramatsu ◽  
Taichi Kuramochi ◽  
Hitoshi Katada ◽  
Atsunori Ueyama ◽  
Yoshinao Ruike ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Transforming Growth Factor ◽  
Muscle Growth ◽  
Transforming Growth Factor Β ◽  
Muscle Disease ◽  
Negative Regulator ◽  
Disease Models ◽  
Muscular Disorders ◽  
Disease Therapy ◽  
Improve Muscle Strength

AbstractMyostatin, a member of the transforming growth factor-β superfamily, is an attractive target for muscle disease therapy because of its role as a negative regulator of muscle growth and strength. Here, we describe a novel antibody therapeutic approach that maximizes the potential of myostatin-targeted therapy. We generated an antibody, GYM329, that specifically binds the latent form of myostatin and inhibits its activation. Additionally, via “sweeping antibody technology”, GYM329 reduces or “sweeps” myostatin in the muscle and plasma. Compared with conventional anti-myostatin agents, GYM329 and its surrogate antibody exhibit superior muscle strength-improvement effects in three different mouse disease models. We also demonstrate that the superior efficacy of GYM329 is due to its myostatin specificity and sweeping capability. Furthermore, we show that a GYM329 surrogate increases muscle mass in normal cynomolgus monkeys without any obvious toxicity. Our findings indicate the potential of GYM329 to improve muscle strength in patients with muscular disorders.

scholarly journals Myostatin expression during development and chronic stress in zebrafish (Danio rerio)

2003 ◽  
Vol 176 (1) ◽  
pp. 47-59 ◽  
Author(s):  
S Vianello ◽  
L Brazzoduro ◽  
L Dalla Valle ◽  
P Belvedere ◽  
L Colombo
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cultured Cells ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Muscle Growth ◽  
Negative Regulator ◽  
Small Fish ◽  
Adult Muscle ◽  
Lateral Muscle

Myostatin, a member of the transforming growth factor-beta superfamily, is a negative regulator of skeletal muscle mass in mammals. We have studied myostatin expression during embryonic and post-hatching development in zebrafish by semiquantitative RT-PCR. The transcript is present in just-fertilized eggs and declines at 8 h post-fertilization (hpf), suggesting a maternal origin. A secondary rise occurs at 16 hpf, indicating the onset of embryonic transcription at the time of muscle cell differentiation. The level of myostatin mRNA decreases slightly at 24 hpf, when somitogenesis is almost concluded, and rises again at and after hatching, during the period of limited muscle hyperplastic growth that is typical of slow-growing, small fish. In the adult muscle, we found the highest expression of myostatin mRNA and protein, which were detectable by Northern and Western blot analyses respectively. Although only the precursor protein form was revealed in the adult lateral muscle, we demonstrated that zebrafish myostatin is proteolytically processed and secreted in cultured cells, as is its mammalian counterpart. These results suggest that myostatin may play an important regulatory role during myogenesis and muscle growth in fish, as it does in mammals. In chronically stressed fish, grown from 16 days post-fertilization to adulthood in an overcrowded environment, we observed both depression of body growth and a diminished level of myostatin mRNA in the adult muscle, as compared with controls. We propose that chronic stunting in fish brings about a general depression of muscle protein synthesis which does not spare myostatin.

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 A Novel Nanobody Directed against Ovine Myostatin to Enhance Muscle Growth in Mouse

Animals ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1398
Author(s):  
Kepeng Ou ◽  
Youjian Li ◽  
Peng Wu ◽  
Jixing Guo ◽  
Xiujing Hao ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Intramuscular Injection ◽  
Transforming Growth Factor ◽  
Muscle Growth ◽  
Domestic Animals ◽  
Negative Regulator ◽  
Promising Treatment ◽  
Animal Growth ◽  
Growth Factor Beta ◽  
Diagnostics And Therapy

Myostatin (MSTN) is a member of the transforming growth factor beta superfamily and is a negative regulator of myogenesis. It has been shown to function by controlling the proliferation of myoblasts. MSTN inhibition is considered as a promising treatment for promoting animal growth in livestock. Nanobodies, a special antibody discovered in camel, have arisen as an alternative to conventional antibodies and have shown great potential when used as tools in different biotechnology fields, such as diagnostics and therapy. In this study, we examined the effect of MSTN inhibition by RMN on the muscle growth of mice. The results showed that RMN could specifically detect and bind MSTN, as well as inhibit MSTN activity. A significant increase in skeletal muscle mass was observed after intramuscular injection of RMN into mice. Enhanced muscle growth occurred because of myofiber hypertrophy. These results offer a promising approach to enhance muscle growth that warrants further investigation in domestic animals.

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 GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone

2020 ◽  
Vol 117 (9) ◽  
pp. 4910-4920 ◽  
Author(s):  
Joonho Suh ◽  
Na-Kyung Kim ◽  
Seung-Hoon Lee ◽  
Je-Hyun Eom ◽  
Youngkyun Lee ◽  
...  
Keyword(s):  
Bone Mass ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Bone Fractures ◽  
Muscle Growth ◽  
Transforming Growth Factor Β ◽  
Biochemical Properties ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Perinatal Lethality

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality ofGdf11null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show thatGdf11null mice, despite significantly down-regulatingMstnexpression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed inMstnnull mice that display enhanced bone mass. Mechanistically,Mstndeletion up-regulatesGdf11expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlikeMstnnull mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

scholarly journals Effect of Oral Anabolic Steroid on Muscle Strength and Muscle Growth in Hemodialysis Patients

2012 ◽  
Vol 8 (2) ◽  
pp. 271-279 ◽  
Author(s):  
Ouppatham Supasyndh ◽  
Bancha Satirapoj ◽  
Pornanong Aramwit ◽  
Duangkamol Viroonudomphol ◽  
Amnart Chaiprasert ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Anabolic Steroid ◽  
Muscle Growth ◽  
Hemodialysis Patients

scholarly journals TGFβ1 Controls PPARγExpression, Transcriptional Potential, and Activity, in Part, through Smad3 Signaling in Murine Lung Fibroblasts

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Allan Ramirez ◽  
Erin N. Ballard ◽  
Jesse Roman
Keyword(s):  
Transforming Growth Factor ◽  
Gene Promoter ◽  
Negative Regulator ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Reporter Expression ◽  
Peroxisome Proliferator Activated Receptor ◽  
3T3 Fibroblasts ◽  
Nih 3T3

Transforming growth factorβ1 (TGFβ1) promotes fibrosis by, among other mechanisms, activating quiescent fibroblasts into myofibroblasts and increasing the expression of extracellular matrices. Recent work suggests that peroxisome proliferator-activated receptorγ(PPARγ) is a negative regulator of TGFβ1-induced fibrotic events. We, however, hypothesized that antifibrotic pathways mediated by PPARγare influenced by TGFβ1, causing an imbalance towards fibrogenesis. Consistent with this, primary murine primary lung fibroblasts responded to TGFβ1 with a sustained downregulation of PPARγtranscripts. This effect was dampened in lung fibroblasts deficient in Smad3, a transcription factor that mediates many of the effects of TGFβ1. Paradoxically, TGFβ1 stimulated the activation of the PPARγgene promoter and induced the phosphorylation of PPARγin primary lung fibroblasts. The ability of TGFβ1 to modulate the transcriptional activity of PPARγwas then tested in NIH/3T3 fibroblasts containing a PPARγ-responsive luciferase reporter. In these cells, stimulation of TGFβ1 signals with a constitutively active TGFβ1 receptor transgene blunted PPARγ-dependent reporter expression induced by troglitazone, a PPARγactivator. Overexpression of PPARγprevented TGFβ1 repression of troglitazone-induced PPARγ-dependent gene transcription, whereas coexpression of PPARγand Smad3 transgenes recapitulated the TGFβ1 effects. We conclude that modulation of PPARγis controlled by TGFβ1, in part through Smad3 signals, involving regulation of PPARγexpression and transcriptional potential.

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