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Smad3 AND Myostatin

Rita De Gasperi, Zachary A Graham, Lauren M Harlow, William A Bauman, Weiping Qin, Christopher P Cardozo
Spinal cord injury (SCI) results in muscle atrophy, reduced force generation and an oxidative-to-glycolytic fiber type shift. The mechanisms responsible for these alterations remain incompletely understood. To gain new insights regarding mechanisms involved in deterioration of muscle after SCI, global expression profiles of miRs in paralyzed gastrocnemius muscle were compared between sham-operated (Sham) and spinal cord-transected (SCI) rats. Ingenuity Pathways Analysis of the altered miRs identified signaling via insulin, IGF-1, integrins and TGF-β as being significantly enriched for target genes...
2016: PloS One
Min Liu, David W Hammers, Elisabeth R Barton, H Lee Sweeney
Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter...
2016: PloS One
W Du, Y Zhang, J Z Yang, H B Li, J Xia, N Li, J S Zhang, X M Yan, Z Y Zhou
Prokaryotic expression technology was used to express maltose-binding protein binding myostatin (MSTN) propeptide fusion protein. Six disease-free Altay lambs were used in this study. The right leg gastrocnemii were injected with MSTN recombinant propeptide protein. The left leg gastrocnemii (the control group) were injected with the same dose of phosphate based saline. The lambs were fed during four months under the same conditions and then slaughtered. Gastrocnemius samples were hematoxylin-eosin stained and the size of the muscle fibers was measured...
June 24, 2016: Genetics and Molecular Research: GMR
A Retamales, R Zuloaga, C A Valenzuela, C Gallardo-Escarate, A Molina, J A Valdés
Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway...
August 21, 2015: Biochemical and Biophysical Research Communications
Xuerong Yang, James E Koltes, Carissa A Park, Daiwen Chen, James M Reecy
Myostatin (Mstn) knockout mice exhibit large increases in skeletal muscle mass. However, relatively few of the genes that mediate or modify MSTN effects are known. In this study, we performed co-expression network analysis using whole transcriptome microarray data from MSTN-null and wild-type mice to identify genes involved in important biological processes and pathways related to skeletal muscle and adipose development. Genes differentially expressed between wild-type and MSTN-null mice were further analyzed for shared DNA motifs using DREME...
2015: PloS One
Daniel Horbelt, Jan H Boergermann, Apirat Chaikuad, Ivan Alfano, Eleanor Williams, Ilya Lukonin, Tobias Timmel, Alex N Bullock, Petra Knaus
GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors...
February 6, 2015: Journal of Biological Chemistry
Rajan Singh, Melissa Braga, Shehla Pervin
Obesity develops from perturbations of cellular bioenergetics, when energy uptake exceeds energy expenditure, and represents a major risk factor for the development of type 2 diabetes, dyslipidemia, cardiovascular disease, cancer, and other conditions. Brown adipose tissue (BAT) has long been known to dissipate energy as heat and contribute to energy expenditure, but its presence and physiological role in adult human physiology has been questioned for years. Recent demonstrations of metabolically active brown fat depots in adult humans have revolutionized current therapeutic approaches for obesity-related diseases...
2014: Frontiers in Cell and Developmental Biology
Ruheena Javed, Lu Jing, Jinzeng Yang, Xinyun Li, Jianhua Cao, Shuhong Zhao
MicroRNAs (miRNAs) play an imperative role in cell proliferation, differentiation, and cell metabolism through regulation of gene expression. Skeletal muscle hypertrophy that results from myostatin depression by its propeptide provides an interesting model to understand how miRNA transcriptome is involved in myostatin-based fiber hypertrophy. This study employed Solexa deep sequencing followed by Q-PCR methods to analyze miRNA transcriptome of skeletal muscle of myostatin propeptide transgenic mice in comparison with their littermate controls...
2014: BioMed Research International
Amrutlal K Patel, Ajai K Tripathi, Utsav A Patel, Ravi K Shah, Chaitanya G Joshi
Myostatin, a negative regulator of skeletal muscle mass, is a proven candidate to modulate skeletal muscle mass through targeted gene knockdown approach. Here, we report myostatin (MSTN) knockdown in goat myoblasts stably expressing small hairpin RNA (shRNAs) against MSTN gene through lentivirus vector-mediated integration. We observed 72% (p = 0.003) and 54% (p = 0.022) downregulation of MSTN expression with sh2 shRNA compared to empty vector control and untransduced myoblasts, respectively. The knockdown of MSTN expression was accompanied with concomitant downregulation of myogenic regulatory factor MYOD (77%, p = 0...
August 2014: In Vitro Cellular & Developmental Biology. Animal
Md Soriful Islam, William H Catherino, Olga Protic, Milijana Janjusevic, Peter Clarke Gray, Stefano Raffaele Giannubilo, Andrea Ciavattini, Pasquale Lamanna, Andrea Luigi Tranquilli, Felice Petraglia, Mario Castellucci, Pasquapina Ciarmela
CONTEXT: Uterine leiomyomas are highly prevalent benign tumors of premenopausal women and the most common indication for hysterectomy. However, the exact etiology of this tumor is not fully understood. OBJECTIVE: The objective of the study was to evaluate the role of activin-A and myostatin and their signaling pathways in human myometrial and leiomyoma cells. DESIGN: This was a laboratory study. SETTING: Myometrial and leiomyoma cells (primary and cell lines) were cultured in vitro...
May 2014: Journal of Clinical Endocrinology and Metabolism
Q J Zeng, L N Wang, G Shu, S B Wang, X T Zhu, P Gao, Q Y Xi, Y L Zhang, Z Q Zhang, Q Y Jiang
Decorin, a small leucine-rich proteoglycan as a component of the extracellular matrix, plays an important role in the skeletal muscle development. It has been reported that decorin promoted proliferation and differentiation of muscle cells by restraining myostatin activity in rodents. However, the effects and mechanisms of decorin on avian myoblast proliferation are not understood clearly. Thus, in our research, decorin overexpressing and knocking-down quail myoblast-7 (QM7) myoblasts were established to explore the effects of decorin on avian myoblast proliferation by flow cytometry...
January 2014: Poultry Science
Craig McFarlane, Anuradha Vajjala, Harikumar Arigela, Sudarsanareddy Lokireddy, XiaoJia Ge, Sabeera Bonala, Ravikumar Manickam, Ravi Kambadur, Mridula Sharma
Growth factors, such as myostatin (Mstn), play an important role in regulating post-natal myogenesis. In fact, loss of Mstn has been shown to result in increased post-natal muscle growth through enhanced satellite cell functionality; while elevated levels of Mstn result in dramatic skeletal muscle wasting through a mechanism involving reduced protein synthesis and increased ubiquitin-mediated protein degradation. Here we show that miR-27a/b plays an important role in feed back auto-regulation of Mstn and thus regulation of post-natal myogenesis...
2014: PloS One
Sabeera Bonala, Sudarsanareddy Lokireddy, Craig McFarlane, Sreekanth Patnam, Mridula Sharma, Ravi Kambadur
To date a plethora of evidence has clearly demonstrated that continued high calorie intake leads to insulin resistance and type-2 diabetes with or without obesity. However, the necessary signals that initiate insulin resistance during high calorie intake remain largely unknown. Our results here show that in response to a regimen of high fat or high glucose diets, Mstn levels were induced in muscle and liver of mice. High glucose- or fat-mediated induction of Mstn was controlled at the level of transcription, as highly conserved carbohydrate response and sterol-responsive (E-box) elements were present in the Mstn promoter and were revealed to be critical for ChREBP (carbohydrate-responsive element-binding protein) or SREBP1c (sterol regulatory element-binding protein 1c) regulation of Mstn expression...
March 14, 2014: Journal of Biological Chemistry
Sandhya Sriram, Subha Subramanian, Prasanna Kumar Juvvuna, Xiaojia Ge, Sudarsanareddy Lokireddy, Craig Desmond McFarlane, Walter Wahli, Ravi Kambadur, Mridula Sharma
Smad (Sma and Mad-related protein) 2/3 are downstream signaling molecules for TGF-β and myostatin (Mstn). Recently, Mstn was shown to induce reactive oxygen species (ROS) in skeletal muscle via canonical Smad3, nuclear factor-κB, and TNF-α pathway. However, mice lacking Smad3 display skeletal muscle atrophy due to increased Mstn levels. Hence, our aims were first to investigate whether Mstn induced muscle atrophy in Smad3(-/-) mice by increasing ROS and second to delineate Smad3-independent signaling mechanism for Mstn-induced ROS...
March 2014: Molecular Endocrinology
Buel D Rodgers, Benjamin D Wiedeback, Knut E Hoversten, Melissa F Jackson, Ryan G Walker, Thomas B Thompson
The immortal C2C12 cell line originates from dystrophic mouse thigh muscle and has been used to study the endocrine control of muscle cell growth, development, and function, including those actions regulated by myostatin. Previous studies suggest that high concentrations of recombinant myostatin generated in bacteria inhibit C2C12 proliferation and differentiation. Recombinant myostatin generated in eukaryotic systems similarly inhibits the proliferation of primary myosatellite cells, but consequently initiates, rather than inhibits, their differentiation and is bioactive at far lower concentrations...
March 2014: Endocrinology
Ferenc Jeanplong, Shelley J Falconer, Jenny M Oldham, Mark Thomas, Tarra S Gray, Alex Hennebry, Kenneth G Matthews, Frederick C Kemp, Ketan Patel, Carole Berry, Gina Nicholas, Christopher D McMahon
Myostatin plays a fundamental role in regulating the size of skeletal muscles. To date, only a single myostatin gene and no splice variants have been identified in mammals. Here we describe the splicing of a cryptic intron that removes the coding sequence for the receptor binding moiety of sheep myostatin. The deduced polypeptide sequence of the myostatin splice variant (MSV) contains a 256 amino acid N-terminal domain, which is common to myostatin, and a unique C-terminus of 65 amino acids. Western immunoblotting demonstrated that MSV mRNA is translated into protein, which is present in skeletal muscles...
2013: PloS One
Estelle Lach-Trifilieff, Giulia C Minetti, KellyAnn Sheppard, Chikwendu Ibebunjo, Jerome N Feige, Steffen Hartmann, Sophie Brachat, Helene Rivet, Claudia Koelbing, Frederic Morvan, Shinji Hatakeyama, David J Glass
The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A...
February 2014: Molecular and Cellular Biology
Chenxi Liu, Wenrong Li, Xuemei Zhang, Ning Zhang, Sangang He, Juncheng Huang, Yubin Ge, Mingjun Liu
Myostatin (MSTN), is a known negative regulator of myogenesis. Silencing of the function of MSTN could result in increasing muscle mass in mice. To determine the function of endogenous MSTN expression on proliferation of sheep myoblasts, a short-hairpin RNA-targeting sheep MSTN was constructed into lentiviral vector to silence endogenous MSTN expression. We demonstrated that silencing of endogenous MSTN gene with up to approximately 73.3% reduction by short hairpin RNA (shRNA) resulted in significant increase (overall 28...
February 2014: In Vitro Cellular & Developmental Biology. Animal
Craig A Goodman, Rachel M McNally, F Michael Hoffmann, Troy A Hornberger
Myostatin, a member of the TGF superfamily, is sufficient to induce skeletal muscle atrophy. Myostatin-induced atrophy is associated with increases in E3-ligase atrogin-1 expression and protein degradation and decreases in Akt/mechanistic target of rapamycin (mTOR) signaling and protein synthesis. Myostatin signaling activates the transcription factor Smad3 (Small Mothers Against Decapentaplegic), which has been shown to be necessary for myostatin-induced atrogin-1 expression and atrophy; however, it is not known whether Smad3 is sufficient to induce these events or whether Smad3 simply plays a permissive role...
November 2013: Molecular Endocrinology
Jaemin Jeong, Michael J Conboy, Irina M Conboy
AIM: To study the influence of acute experimental diabetes on the regenerative potential of muscle stem (satellite) cells in mice. METHODS: Male C57BL/6 young mice were injected with a single dose of streptozotocin (STZ, 180 mg/kg, ip) to induce diabetes. The diabetic mice were treated with insulin (0.75 U/kg, ip), follistatin (12 μg/kg, im) or Alk5 inhibitor (5 μmol/L per kg, sc) once a day. On the first day when high glucose levels were found, cardiotoxin (CTX) was focally injected into tibialis anterior and gastronemius muscles of the mice...
August 2013: Acta Pharmacologica Sinica
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