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Myostatin inhibitors

P R Chen, K Lee
With the increasing demand for affordable, high-quality meat, livestock and poultry producers must continually find ways to maximize muscle growth in their animals without compromising palatability of the meat products. Muscle mass relies on myoblast proliferation during prenatal or prehatch stages and fiber hypertrophy through protein synthesis and nuclei donation by satellite cells after birth or hatch. Therefore, understanding the cellular and molecular mechanisms of myogenesis and muscle development is of great interest...
August 2016: Journal of Animal Science
Joaquim Fernández-Solà, Ana Planavila Porta
High-dose alcohol misuse induces multiple noxious cardiac effects, including myocyte hypertrophy and necrosis, interstitial fibrosis, decreased ventricular contraction and ventricle enlargement. These effects produce diastolic and systolic ventricular dysfunction leading to congestive heart failure, arrhythmias and an increased death rate. There are multiple, dose-dependent, synchronic and synergistic mechanisms of alcohol-induced cardiac damage. Ethanol alters membrane permeability and composition, interferes with receptors and intracellular transients, induces oxidative, metabolic and energy damage, decreases protein synthesis, excitation-contraction coupling and increases cell apoptosis...
September 29, 2016: International Journal of Molecular Sciences
Alexandra C Braun, Marcus Gutmann, Regina Ebert, Franz Jakob, Henning Gieseler, Tessa Lühmann, Lorenz Meinel
PURPOSE: The inhibition of myostatin - a member of the transforming growth factor (TGF-β) family - drives regeneration of functional skeletal muscle tissue. We developed a bioresponsive drug delivery system (DDS) linking release of a myostatin inhibitor (MI) to inflammatory flares of myositis to provide self-regulated MI concentration gradients within tissues of need. METHODS: A protease cleavable linker (PCL) - responding to MMP upregulation - is attached to the MI and site-specifically immobilized on microparticle surfaces...
September 14, 2016: Pharmaceutical Research
Agnese Collamati, Emanuele Marzetti, Riccardo Calvani, Matteo Tosato, Emanuela D'Angelo, Alex N Sisto, Francesco Landi
Chronic heart failure (CHF) is a highly prevalent condition among the elderly and is associated with considerable morbidity, institutionalization and mortality. In its advanced stages, CHF is often accompanied by the loss of muscle mass and strength. Sarcopenia is a geriatric syndrome that has been actively studied in recent years due to its association with a wide range of adverse health outcomes. The goal of this review is to discuss the relationship between CHF and sarcopenia, with a focus on shared pathophysiological pathways and treatments...
July 2016: Journal of Geriatric Cardiology: JGC
Yuki Enoki, Hiroshi Watanabe, Riho Arake, Ryusei Sugimoto, Tadashi Imafuku, Yuna Tominaga, Yu Ishima, Shunsuke Kotani, Makoto Nakajima, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama
Skeletal muscle atrophy, referred to as sarcopenia, is often observed in chronic kidney disease (CKD) patients, especially in patients who are undergoing hemodialysis. The purpose of this study was to determine whether uremic toxins are involved in CKD-related skeletal muscle atrophy. Among six protein-bound uremic toxins, indole containing compounds, indoxyl sulfate (IS) significantly inhibited proliferation and myotube formation in C2C12 myoblast cells. IS increased the factors related to skeletal muscle breakdown, such as reactive oxygen species (ROS) and inflammatory cytokines (TNF-α, IL-6 and TGF-β1) in C2C12 cells...
2016: Scientific Reports
Adam P Lightfoot, Robert G Cooper
PURPOSE OF REVIEW: This article updates on the concept that muscle-derived cytokines (myokines) play important roles in muscle health and disease. RECENT FINDINGS: Interleukin-6 (IL-6) is released from normal skeletal muscle in response to exercise, mediating both anti-inflammatory responses and metabolic adaptations, actions contradictory to the prevailing view that IL-6 is a proinflammatory cytokine that is inducing and propagating disease. The anti-inflammatory effects of IL-6 result from its trans-membrane signalling capability, via membrane-bound receptors, whereas its proinflammatory effects result instead from signalling via the soluble IL-6 receptor and gp130...
November 2016: Current Opinion in Rheumatology
Craig Campbell, Hugh J McMillan, Jean K Mah, Mark Tarnopolsky, Kathryn Selby, Ty McClure, Dawn M Wilson, Matthew L Sherman, Diana Escolar, Kenneth M Attie
INTRODUCTION: ACE-031 is a fusion protein of activin receptor type IIB and IgG1-Fc, which binds myostatin. It aims to disrupts its inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). METHODS: ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo-controlled, ascending dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics...
July 27, 2016: Muscle & Nerve
Shinji Hatakeyama, Serge Summermatter, Marie Jourdain, Stefan Melly, Giulia C Minetti, Estelle Lach-Trifilieff
BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. METHODS: In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model...
2016: Skeletal Muscle
Nicholas J Galt, Stephen D McCormick, Jacob Michael Froehlich, Peggy R Biga
Cortisol, the primary corticosteroid in teleost fishes, is released in response to stressors to elicit local functions, however little is understood regarding muscle-specific responses to cortisol in these fishes. In mammals, glucocorticoids strongly regulate the muscle growth inhibitor, myostatin, via glucocorticoid response elements (GREs) leading to muscle atrophy. Bioinformatics methods suggest that this regulatory mechanism is conserved among vertebrates, however recent evidence suggests some fishes exhibit divergent regulation...
October 1, 2016: General and Comparative Endocrinology
Anders Rasmussen Rinnov, Peter Plomgaard, Bente Klarlund Pedersen, Lise Lotte Gluud
CONTEXT: Follistatin is a liver-derived inhibitor of the muscle-growth inhibitor myostatin. Reduction in acute follistatin release may help explain muscle loss in liver cirrhosis. OBJECTIVE: The study aimed to investigate the capacity of acute follistatin release in patients with liver cirrhosis compared to healthy control participants. DESIGN, SETTING, AND PARTICIPANTS: To experimentally increase the glucagon-insulin ratio (mimicking the hormonal effect of exercise), we infused glucagon/somatostatin (to inhibit insulin secretion) and compared the acute follistatin increase in eight male cirrhosis patients with eight healthy control participants...
September 2016: Journal of Clinical Endocrinology and Metabolism
Javier Angulo, Mariam El Assar, Leocadio Rodríguez-Mañas
Frailty is a functional status that precedes disability and is characterized by decreased functional reserve and increased vulnerability. In addition to disability, the frailty phenotype predicts falls, institutionalization, hospitalization and mortality. Frailty is the consequence of the interaction between the aging process and some chronic diseases and conditions that compromise functional systems and finally produce sarcopenia. Many of the clinical manifestations of frailty are explained by sarcopenia which is closely related to poor physical performance...
August 2016: Molecular Aspects of Medicine
Liang Wang, Ting Zhang, Yongyong Xi, Cuili Yang, Chengcao Sun, Dejia Li
Accumulating evidence suggests that Sirtuin (Sirt)1 serves a significant role in proliferation and differentiation of myoblast cells; however the signaling mechanisms involved remain to be established. Myostatin (MSTN), a member of transforming growth factor‑β family, is an vital regulator of myoblast, fibroblast growth and differentiation. To determine if MSTN is involved in the regulation of myoblast cell proliferation by Sirt1, the present study administrated the Sirt1 activator resveratrol, inhibitor nicotinamide (NAM) and MSTN inhibitor SB431542 to C2C12 myoblast cells...
August 2016: Molecular Medicine Reports
L Liu, Y L Li, S D Xu, K Z Wang, P Wu, W Y Chu, X Q Wang
Myostatin (MSTN) is an important member of the transforming growth factor-β (TGF-β) superfamily and is a muscle growth inhibitor. In the present study, we cloned the Chinese perch MSTN cDNA sequence and analyzed its expression patterns under various conditions. The MSTN full cDNA sequence was 3347 bp long, including an open-reading frame of 1131 bp, which encoded 376 amino acids. Sequence analysis demonstrated that the MSTN shared a highly conserved signal peptide, a TGF-β functional peptide, a hydrolytic site (RARR), and nine conservative cysteine residues with other members of the TGF-β superfamily...
2016: Genetics and Molecular Research: GMR
Shuai Liu, XiaoQun Liu, HaiYan Huang, QingYou Liu, XiaoPing Su, Peng Zhu, HongLi Li, KuiQing Cui, BingKun Xie, DeShun Shi
Cytoplasmic microinjection (CI) of foreign gene into in vivo fertilized zygotes has emerged as a useful tool for transgenic pig production. In the current study, we investigated factors affecting transgenic efficiency and developmental potential of parthenogenetic (PA) and in vitro-fertilized (IVF) porcine embryos produced by CI. These factors included adding of RNase inhibitor, DNA or RNA concentration, injection time, and different structures of plasmids. Our results showed that adding of 1-4 U/μL of RNase inhibitor did not have negative effect on development potential of CI-PA embryos, and RNase inhibitor injection significantly increased EGFP expressing rate of CI-PA embryos...
August 2016: In Vitro Cellular & Developmental Biology. Animal
Jennifer Tinklenberg, Hui Meng, Lin Yang, Fujun Liu, Raymond G Hoffmann, Mahua Dasgupta, Kenneth P Allen, Alan H Beggs, Edna C Hardeman, R Scott Pearsall, Robert H Fitts, Michael W Lawlor
Nemaline myopathies (NMs) are a group of congenital muscle diseases caused by mutations in at least 10 genes and associated with a range of clinical symptoms. NM is defined on muscle biopsy by the presence of cytoplasmic rod-like structures (nemaline rods) composed of cytoskeletal material. Myofiber smallness is also found in many cases of NM and may represent a cause of weakness that can be counteracted by treatment. We have used i.p. injection of activin type IIB receptor (ActRIIB)-mFc (an inhibitor of myostatin signaling) to promote hypertrophy and increase strength in our prior murine work; we therefore tested whether ActRIIB-mFc could improve weakness in NM mice through myofiber hypertrophy...
June 2016: American Journal of Pathology
Eun Ju Lee, Arif Tasleem Jan, Mohammad Hassan Baig, Jalaluddin Mohammad Ashraf, Sang-Soep Nahm, Yong-Woon Kim, So-Young Park, Inho Choi
Differentiation of muscle satellite cells (MSCs) involves interaction of the proteins present in the extracellular matrix (ECM) with MSCs to regulate their activity, and therefore phenotype. Herein, we report fibromodulin (FMOD), a member of the proteoglycan family participating in the assembly of ECM, as a novel regulator of myostatin (MSTN) during myoblast differentiation. In addition to having a pronounced effect on the expression of myogenic marker genes [myogenin (MYOG) and myosin light chain 2 (MYL2)], FMOD was found to maintain the transcriptional activity of MSTN Moreover, coimmunoprecipitation and in silico studies performed to investigate the interaction of FMOD helped confirm that it antagonizes MSTN function by distorting its folding and preventing its binding to activin receptor type IIB...
August 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Joe N Kornegay, Daniel J Bogan, Janet R Bogan, Jennifer L Dow, Jiahui Wang, Zheng Fan, Naili Liu, Leigh C Warsing, Robert W Grange, Mihye Ahn, Cynthia J Balog-Alvarez, Steven W Cotten, Monte S Willis, Candice Brinkmeyer-Langford, Hongtu Zhu, Joe Palandra, Carl A Morris, Martin A Styner, Kathryn R Wagner
BACKGROUND: Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition...
2016: Skeletal Muscle
Stephen J Shepherd, Richard Newman, Stephen J Brett, David M Griffith
OBJECTIVES: ICU-acquired weakness is a common complication of critical illness and can have significant effects upon functional status and quality of life. As part of preliminary work to inform the design of a randomized trial of a complex intervention to improve recovery from critical illness, we sought to identify pharmacological interventions that may play a role in this area. DATA SOURCES: We systematically reviewed the published literature relating to pharmacological intervention for the treatment and prevention of ICU-acquired weakness...
June 2016: Critical Care Medicine
Kentaro Takayama, Akari Nakamura, Cédric Rentier, Yusaku Mino, Tomo Asari, Yusuke Saga, Akihiro Taguchi, Fumika Yakushiji, Yoshio Hayashi
Inhibition of myostatin, which negatively regulates skeletal muscle growth, is a promising strategy for the treatment of muscle atrophic disorders, such as muscular dystrophy, cachexia and sarcopenia. Recently, we identified peptide A (H-WRQNTRYSRIEAIKIQILSKLRL-NH2 ), the 23-amino-acid minimum myostatin inhibitory peptide derived from mouse myostatin prodomain, and highlighted the importance of its N-terminal tryptophan residue for the effective inhibition. In this study, we synthesized a series of acylated peptide derivatives focused on the tryptophan residue to develop potent myostatin inhibitors...
April 19, 2016: ChemMedChem
Anil K Padyana, Bhamini Vaidialingam, David B Hayes, Priyanka Gupta, Michael Franti, Neil A Farrow
Members of the TGF-β family of proteins are believed to play critical roles in cellular signaling processes such as those involved in muscle differentiation. The extent to which individual family members have been characterized and linked to biological function varies greatly. The role of myostatin, also known as growth differentiation factor 8 (GDF8), as an inhibitor of muscle differentiation is well understood through genetic linkages. In contrast, the role of growth differentiation factor 11 (GDF11) is much less well understood...
March 2016: Acta Crystallographica. Section F, Structural Biology Communications
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