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Myostatin human

P Singh, H Rong, T Gordi, J Bosley, I Bhattacharya
Suppression of the myostatin (GDF-8) pathway has emerged as an important therapeutic paradigm for muscle-wasting disorders. In this study, we conducted a translational pharmacokinetic/pharmacodynamic (PK/PD) analysis of MYO-029, an anti-myostatin monoclonal antibody, using PK data in mice, rats, monkeys, humans, mouse tissue distribution data with (125) I-labeled MYO-029, muscle weight increase in SCID mice, and muscle circumference changes in monkeys. This analysis revealed significant in vivo potency shift between mice and monkeys (72 nM vs...
October 4, 2016: Clinical and Translational Science
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
James R Apgar, Michelle Mader, Rita Agostinelli, Susan Benard, Peter Bialek, Mark Johnson, Yijie Gao, Mark Krebs, Jane Owens, Kevin Parris, Michael St Andre, Kris Svenson, Carl Morris, Lioudmila Tchistiakova
Antibodies are an important class of biotherapeutics that offer specificity to their antigen, long half-life, effector function interaction and good manufacturability. The immunogenicity of non-human-derived antibodies, which can be a major limitation to development, has been partially overcome by humanization through complementarity-determining region (CDR) grafting onto human acceptor frameworks. The retention of foreign content in the CDR regions, however, is still a potential immunogenic liability. Here, we describe the humanization of an anti-myostatin antibody utilizing a 2-step process of traditional CDR-grafting onto a human acceptor framework, followed by a structure-guided approach to further reduce the murine content of CDR-grafted antibodies...
September 13, 2016: MAbs
Javier Barallobre-Barreiro, Shashi K Gupta, Anna Zoccarato, Rika Kitazume-Taneike, Marika Fava, Xiaoke Yin, Tessa Werner, Marc N Hirt, Anna Zampetaki, Alessandro Viviano, Mei Chong, Marshall Bern, Antonios Kourliouros, Nieves Domenech, Peter Willeit, Ajay M Shah, Marjan Jahangiri, Liliana Schaefer, Jens W Fischer, Renato V Iozzo, Rosa Viner, Thomas Thum, Joerg Heineke, Antoine Kichler, Kinya Otsu, Manuel Mayr
BACKGROUND: Myocardial fibrosis is a feature of many cardiac diseases. We used proteomics to profile glycoproteins in the human cardiac extracellular matrix (ECM). METHODS: Atrial specimens were analyzed by mass spectrometry after extraction of ECM proteins and enrichment for glycoproteins or glycopeptides. RESULTS: ECM-related glycoproteins were identified in left and right atrial appendages from the same patients. Several known glycosylation sites were confirmed...
September 13, 2016: Circulation
Neil A Schwarz, Sarah K McKinley-Barnard, Mike B Spillane, Thomas L Andre, Joshua J Gann, Darryn S Willoughby
The purpose of this study was to investigate the acute messenger (mRNA) expression of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) isoforms, insulin-like growth factor-1Ea (IGF-1Ea), and myostatin in response to 2 resistance exercise intensities. In a uniform-balanced, crossover design, 10 participants performed 2 separate testing sessions involving a lower body resistance exercise component consisting of a lower intensity (50% of 1-repetition maximum; 1RM) protocol and a higher intensity (80% of 1RM) protocol of equal volumes...
August 2016: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
Marissa J Schafer, Elizabeth J Atkinson, Patrick M Vanderboom, Brian Kotajarvi, Thomas A White, Matthew M Moore, Charles J Bruce, Kevin L Greason, Rakesh M Suri, Sundeep Khosla, Jordan D Miller, H Robert Bergen, Nathan K LeBrasseur
Growth and differentiation factor 11 (GDF11) is a transforming growth factor β superfamily member with a controversial role in aging processes. We have developed a highly specific LC-MS/MS assay to quantify GDF11, resolved from its homolog, myostatin (MSTN), based on unique amino acid sequence features. Here, we demonstrate that MSTN, but not GDF11, declines in healthy men throughout aging. Neither GDF11 nor MSTN levels differ as a function of age in healthy women. In an independent cohort of older adults with severe aortic stenosis, we show that individuals with higher GDF11 were more likely to be frail and have diabetes or prior cardiac conditions...
June 14, 2016: Cell Metabolism
Gonzalo Perez-Siles, Adrienne Grant, Melina Ellis, Carolyn Ly, Aditi Kidambi, Mamdouh Khalil, Roxana M Llanos, Sharon La Fontaine, Alleene V Strickland, Stephan Züchner, Sandra Bermeo, Elysia Neist, Tara C Brennan-Speranza, Reinaldo I Takata, Carlos E Speck-Martins, Julian F B Mercer, Garth A Nicholson, Marina L Kennerson
ATP7A is a P-type ATPase essential for cellular copper (Cu) transport and homeostasis. Loss-of-function ATP7A mutations causing systemic Cu deficiency are associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome. We previously identified two rare ATP7A missense mutations (P1386S and T994I) leading to a non-fatal form of motor neuron disorder, X-linked distal hereditary motor neuropathy (dHMNX), without overt signs of systemic Cu deficiency. Recent investigations using a tissue specific Atp7a knock out model have demonstrated that Cu plays an essential role in motor neuron maintenance and function, however the underlying pathogenic mechanisms of ATP7A mutations causing axonal degeneration remain unknown...
September 1, 2016: Metallomics: Integrated Biometal Science
Ana Belén Gómez-SanMiguel, Carolina Gomez-Moreira, María Paz Nieto-Bona, Carmen Fernández-Galaz, Maria Ángeles Villanúa, Ana Isabel Martín, Asunción López-Calderón
Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. β2-adrenergic receptor agonists are powerful anabolic agents that trigger skeletal muscle hypertrophy and have been proposed as a promising treatment for muscle wasting in human patients. The aim of this work was to determine whether formoterol, a selective β2-adrenoreceptor agonist, is able to ameliorate muscle wasting in arthritic rats. Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant...
June 1, 2016: American Journal of Physiology. Endocrinology and Metabolism
X Duan, W Ji, B Dong, G Sun, Y Bian
Insulin-like growth factor-I (IGF-I) and myostatin (MSTN) are a pair of critical positive and negative growth regulators. The aim of the current study was to examine the age-dependent and muscle-specific expression of IGF-I and MSTN mRNAs in black Muscovy ducks in order to understand their roles in regulating the postnatal muscle growth of domestic ducks. The full-length cDNA of the black Muscovy duck MSTN gene was cloned and the age-dependent mRNA expression profile was compared with that of the IGF-I mRNA in skeletal muscles...
October 2016: British Poultry Science
Kay-Marie Lamar, Sasha Bogdanovich, Brandon B Gardner, Quan Q Gao, Tamari Miller, Judy U Earley, Michele Hadhazy, Andy H Vo, Lisa Wren, Jeffery D Molkentin, Elizabeth M McNally
Latent TGFβ binding proteins (LTBPs) regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter...
May 2016: PLoS Genetics
Domenico Di Raimondo, Antonino Tuttolomondo, Gaia Musiari, Caterina Schimmenti, Alessandra D'Angelo, Antonio Pinto
BACKGROUND: The concept of the muscle as a secretory organ, developed during the last decades, partially answers to the issue of how the crosstalk between skeletal muscle and distant tissues happens. The beneficial effects of exercise transcend the simple improved skeletal muscle functionality: systemic responses to exercise have been observed in distal organs like heart, kidney, brain and liver. Increasing data have accumulated regarding the synthesis, the kinetics of release and the biological roles of muscular cytokines, now called myokines...
2016: Current Pharmaceutical Design
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
Hala Aswad, Audrey Jalabert, Sophie Rome
BACKGROUND: Fetal bovine serum (FBS) contains a wide range of growth factors, hormones, vitamins, amino acids, fatty acids and trace elements required for cell growth. It was shown that animal sera contain also extracellular vesicles (EVs) with important biological properties; thus we wondered whether EVs present in FBS would influence muscle cell phenotype. EVs were removed from sera by ultracentrifugation (18 h). C2C12, L6 and human primary myoblasts, were grown either in classical media (CM) or in EVs-depleted media...
2016: BMC Biotechnology
Ryan G Walker, Tommaso Poggioli, Lida Katsimpardi, Sean M Buchanan, Juhyun Oh, Sam Wattrus, Bettina Heidecker, Yick W Fong, Lee L Rubin, Peter Ganz, Thomas B Thompson, Amy J Wagers, Richard T Lee
Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes...
April 1, 2016: Circulation Research
Wanchang Cui, Alexander W Bennett, Pei Zhang, Kory R Barrow, Sean R Kearney, Kim G Hankey, Cheryl Taylor-Howell, Allison M Gibbs, Cassandra P Smith, Thomas J MacVittie
Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20-25% was observed which was refractory to nutritional intervention...
2016: Scientific Reports
L Woodhouse, R Gandhi, S J Warden, S Poiraudeau, S L Myers, C T Benson, L Hu, Q I Ahmad, P Linnemeier, E V Gomez, O Benichou
BACKGROUND: Total hip arthroplasty relieves joint pain in patients with end stage osteoarthritis. However, postoperative muscle atrophy often results in suboptimal lower limb function. There is a need to improve functional recovery after total hip arthroplasty. OBJECTIVES: To assess safety and efficacy of LY2495655, a humanized monoclonal antibody targeting myostatin, in patients undergoing elective total hip arthroplasty. DESIGN: Phase 2, randomized, parallel, double-blind, 12-week clinical trial with a 12-week follow-up period...
2016: Journal of Frailty & Aging
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
A Costagliola, S Wojcik, T B Pagano, D De Biase, V Russo, V Iovane, E Grieco, S Papparella, O Paciello
Sarcopenia, the age-related loss of muscle mass and strength, is a multifactorial condition that represents a major healthcare concern for the elderly population. Although its morphologic features have been extensively studied in humans, animal models, and domestic and wild animals, only a few reports about spontaneous sarcopenia exist in other long-lived animals. In this work, muscle samples from 60 healthy Podolica-breed old cows (aged 15-23 years) were examined and compared with muscle samples from 10 young cows (3-6 years old)...
March 2016: Veterinary Pathology
Jinxue Ruan, Yuanyuan Zhang, Jing Yuan, Leilei Xin, Jihan Xia, Nan Liu, Yulian Mu, Yaoxing Chen, Shulin Yang, Kui Li
Skeletal muscle is as an important regulator of blood glucose and glycolipid metabolism and is closely related to motor ability. The underlying mechanisms by which dietary ectopic lipids in skeletal muscle prevents muscle growth remain elusive. We utilized miniature Bama swine as a model to mimic human obesity using prolonged dietary induction. After 23 months on a high-fat, high-sucrose diet, metabolic disorders were induced in the animals, which exhibited increased body weight, extensive lipid deposition in the skeletal muscle and amyotrophy...
April 15, 2016: Molecular and Cellular Endocrinology
Mario Thevis, Wilhelm Schänzer
RATIONALE: A plethora of compounds potentially leading to drug candidates that affect skeletal muscle function and, more specifically, mitochondrial biogenesis, has been under (pre)clinical investigation for rare as well as more common diseases. Some of these compounds could be the object of misuse by athletes aiming at artificial and/or illicit and drug-facilitated performance enhancement, necessitating preventive and proactive anti-doping measures. METHODS: Early warnings and the continuous retrieval and dissemination of information are crucial for sports drug testing laboratories as well as anti-doping authorities, as they assist in preparation of efficient doping control analytical strategies for potential future threats arising from new therapeutic developments...
March 15, 2016: Rapid Communications in Mass Spectrometry: RCM
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