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 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 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 OTUD4 enhances TGFβ signalling through regulation of the TGFβ receptor complex

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick William Jaynes ◽  
Prasanna Vasudevan Iyengar ◽  
Sarah Kit Leng Lui ◽  
Tuan Zea Tan ◽  
Natali Vasilevski ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Deubiquitinating Enzyme ◽  
Tgfβ Receptor ◽  
Tgfβ Signalling ◽  
Systematic Control ◽  
General Regulation ◽  
Tgfβ Pathway ◽  
Transcriptional Target

Abstract Systematic control of the transforming growth factor-β (TGFβ) pathway is essential to keep the amplitude and the intensity of downstream signalling at appropriate levels. Ubiquitination plays a crucial role in the general regulation of this pathway. Here we identify the deubiquitinating enzyme OTUD4 as a transcriptional target of the TGFβ pathway that functions through a positive feedback loop to enhance overall TGFβ activity. Interestingly we demonstrate that OTUD4 functions through both catalytically dependent and independent mechanisms to regulate TGFβ activity. Specifically, we find that OTUD4 enhances TGFβ signalling by promoting the membrane presence of TGFβ receptor I. Furthermore, we demonstrate that OTUD4 inactivates the TGFβ negative regulator SMURF2 suggesting that OTUD4 regulates multiple nodes of the TGFβ pathway to enhance TGFβ activity.

scholarly journals Vascular consequences of dietary salt intake

2009 ◽  
Vol 297 (2) ◽  
pp. F237-F243 ◽  
Author(s):  
Paul W. Sanders
Keyword(s):  
Nitric Oxide ◽  
Renal Function ◽  
Life Span ◽  
Vascular Function ◽  
Transforming Growth Factor ◽  
Salt Intake ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Dietary Salt ◽  
Dietary Salt Intake

Animal and human studies support an untoward effect of excess dietary NaCl (salt) intake on cardiovascular and renal function and life span. Recent work has promoted the concept that the endothelium, in particular, reacts to changes in dietary salt intake through a complex series of events that are independent of blood pressure and the renin-angiotensin-aldosterone axis. The cellular signaling events culminate in the intravascular production of transforming growth factor-β (TGF-β) and nitric oxide in response to increased salt intake. Plasticity of the endothelium is integral in the vascular remodeling consequences associated with excess salt intake, because nitric oxide serves as a negative regulator of TGF-β production. Impairment of nitric oxide production, such as occurs with endothelial dysfunction in a variety of disease states, results in unopposed excess vascular TGF-β production, which promotes reduced vascular compliance and augmented peripheral arterial constriction and hypertension. Persistent alterations in vascular function promote the increase in cardiovascular events and reductions in renal function that reduce life span during increased salt intake.

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.

P1226MITOCHONIC ACID 5 (MA-5) AMELIORATES CG-INDUCED PERITONEAL FIBROSIS IN MICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Hiro Inoue ◽  
Yoko Obata ◽  
Takehiro Suzuki ◽  
Miki Torigoe ◽  
Kenta Torigoe ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Parietal Peritoneum ◽  
Disease Models ◽  
Peritoneal Fibrosis ◽  
Chemotactic Protein

Abstract Background and Aims Peritoneal fibrosis is one of important complications induced by long-term peritoneal dialysis. Mitochondrial dysfunction causes an increase of oxidative stress and depletion of ATP. Thus, it may be associated with a variety of disease including fibrosis in several organs. Recently, mitochonic acid 5 (MA-5) was synthesized and its therapeutic potential for mitochondrial dysfunction in kidney disease models has been reported. In this study, we investigated the effect of MA-5 for peritoneal fibrosis model in mice. Method Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) every other day for 3 weeks in C57/BL6 mice. MA-5 was administered at 2 mg/kg by gavage every day from the initiation of CG injection. Control mice received only a vehicle (distilled water). After 3 weeks of treatment, the animals were sacrificed and the peritoneal tissues were collected. The peritoneal sections were stained with Masson’s trichrome for light microscopic examination and the fibrotic thickening of parietal peritoneum was measured on the randomly selected different regions on each section. The expressions of F4/80, which is a marker of macrophages, monocyte chemotactic protein 1 (MCP1), α-smooth muscle actin (α-SMA), and transforming growth factor-β (TGF-β) were evaluated by immunohistochemistry. Results The fibrotic thickening of parietal peritoneum was significantly attenuated in MA-5 treated mice compared with control mice (the thickness of submesothelial area: 100.24 +/- 13.67 vs 54.78 +/- 7.43 μm (p&lt;0.05)). The numbers of TGF-β positive cells, α-SMA positive cells, MCP1 positive cells and infiltrating macrophages were significantly decreased in MA-5 treated mice than those in control mice. Conclusion These results suggest that MA-5 may have a therapeutic potential in the progression of peritoneal fibrosis as well as kidney disease models.

scholarly journals Role of transforming growth factor-β in hematologic malignancies

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4589-4596 ◽  
Author(s):  
Mei Dong ◽  
Gerard C. Blobe
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Myeloproliferative Disorders ◽  
Transforming Growth Factor Β ◽  
Hematologic Malignancies ◽  
Negative Regulator ◽  
Cellular Processes ◽  
Signaling Field

AbstractThe transforming growth factor-β (TGF-β) signaling pathway is an essential regulator of cellular processes, including proliferation, differentiation, migration, and cell survival. During hematopoiesis, the TGF-β signaling pathway is a potent negative regulator of proliferation while stimulating differentiation and apoptosis when appropriate. In hematologic malignancies, including leukemias, myeloproliferative disorders, lymphomas, and multiple myeloma, resistance to these homeostatic effects of TGF-β develops. Mechanisms for this resistance include mutation or deletion of members of the TGF-β signaling pathway and disruption of the pathway by oncoproteins. These alterations define a tumor suppressor role for the TGF-β pathway in human hematologic malignancies. On the other hand, elevated levels of TGF-β can promote myelofibrosis and the pathogenesis of some hematologic malignancies through their effects on the stroma and immune system. Advances in the TGF-β signaling field should enable targeting of the TGF-β signaling pathway for the treatment of hematologic malignancies.

scholarly journals Heat Shock Protein 70 Negatively Regulates TGF-β-Stimulated VEGF Synthesis via p38 MAP Kinase in Osteoblasts

2017 ◽  
Vol 44 (3) ◽  
pp. 1133-1145 ◽  
Author(s):  
Go Sakai ◽  
Haruhiko Tokuda ◽  
Kazuhiko Fujita ◽  
Shingo Kainuma ◽  
Tetsu Kawabata ◽  
...  
Keyword(s):  
Growth Factor ◽  
Heat Shock ◽  
Map Kinase ◽  
Transforming Growth Factor ◽  
Mrna Level ◽  
Transforming Growth Factor Β ◽  
P38 Map Kinase ◽  
Negative Regulator ◽  
Vegf Mrna ◽  
Vegf Release

Background/Aims: We previously demonstrated that transforming growth factor-β (TGF-β) stimulates the synthesis of vascular endothelial growth factor (VEGF) through the activation of p38 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. Heat shock protein70 (HSP70) is a ubiquitously expressed molecular chaperone. In the present study, we investigated the involvement of HSP70 in the TGF-β-stimulated VEGF synthesis and the underlying mechanism in these cells. Methods: Culture MC3T3-E1 cells were stimulated by TGF-β. Released VEGF was measured using an ELISA assay. VEGF mRNA level was quantified by RT-PCR. Phosphorylation of each protein kinase was analyzed by Western blotting. Results: VER-155008 and YM-08, both of HSP70 inhibitors, significantly amplified the TGF-β-stimulated VEGF release. In addition, the expression level of VEGF mRNA induced by TGF-β was enhanced by VER-155008. These inhibitors markedly strengthened the TGF-β-induced phosphorylation of p38 MAP kinase. The TGF-β-induced phosphorylation of p38 MAP kinase was amplified in HSP70-knockdown cells. SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by these inhibitors of the TGF-β-induced VEGF release. Conclusion: These results strongly suggest that HSP70 acts as a negative regulator in the TGF-β-stimulated VEGF synthesis in osteoblasts, and that the inhibitory effect of HSP70 is exerted at a point upstream of p38 MAP kinase.

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