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Myostatin inhibitors

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https://www.readbyqxmd.com/read/28765418/the-emergence-of-sarcopenia-as-an-important-entity-in-older-people
#1
Natalie J Offord, Miles D Witham
Sarcopenia refers to the loss of muscle mass and strength seen with advancing age. The pathophysiology is multifactorial, with loss of muscle satellite cells, changes in hormonal systems, chronic inflammation, oxidative stress and anabolic resistance to protein utilisation all implicated. Older age, female sex and immobility are important risk factors. Sarcopenia is clinically important as it is a major risk factor for physical frailty, falls, prolonged hospitalisation, dependency and earlier death. Diagnosis requires evidence of reduced muscle mass measured by handgrip strength or walk speed, together with evidence of low muscle mass, measured by one of a variety of techniques such as bioimpedance analysis or dual X-ray absorptiometry...
July 2017: Clinical Medicine: Journal of the Royal College of Physicians of London
https://www.readbyqxmd.com/read/28745831/osteopontin-is-linked-with-akt-foxo1-and-myostatin-in-skeletal-muscle-cells
#2
Peter P Nghiem, Joe N Kornegay, Kitipong Uaesoontrachoon, Luca Bello, Ying Yin, Akanchha Kesari, Priya Mittal, Scott J Schatzberg, Gina M Many, Norman H Lee, Eric P Hoffman
INTRODUCTION: Osteopontin (OPN) polymorphisms are associated with muscle size and modify disease progression in Duchenne muscular dystrophy (DMD). We hypothesized that OPN may share a molecular network with myostatin (MSTN). METHODS: Studies were conducted in the golden retriever (GRMD) and mdx mouse models of DMD. Follow-up in-vitro studies were employed in myogenic cells and the mdx mouse treated with recombinant mouse (rm) or human (Hu) OPN protein. RESULTS: OPN was increased and MSTN was decreased and levels correlated inversely in GRMD hypertrophied muscle...
July 26, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/28742154/lipopolysaccharide-inhibits-myogenic-differentiation-of-c2c12-myoblasts-through-the-toll-like-receptor-4-nuclear-factor-%C3%AE%C2%BAb-signaling-pathway-and-myoblast-derived-tumor-necrosis-factor-%C3%AE
#3
Yuko Ono, Kazuho Sakamoto
BACKGROUND: Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or with various endogenous diseases that are associated with metabolic endotoxemia. Involuntary loss of skeletal muscle, termed muscle wasting, is commonly observed in these conditions, suggesting that circulating LPS might play an essential role in its development. Although impairment of muscle regeneration is an important determinant of skeletal muscle wasting, it is unclear whether LPS affects this process and, if so, by what mechanism...
2017: PloS One
https://www.readbyqxmd.com/read/28740611/development-of-potent-myostatin-inhibitory-peptides-through-hydrophobic-residue-directed-structural-modification
#4
Kentaro Takayama, Cédric Rentier, Tomo Asari, Akari Nakamura, Yusuke Saga, Takahiro Shimada, Kei Nirasawa, Eri Sasaki, Kyohei Muguruma, Akihiro Taguchi, Atsuhiko Taniguchi, Yoichi Negishi, Yoshio Hayashi
Myostatin, a negative regulator of skeletal muscle growth, is a promising target for treating muscle atrophic disorders. Recently, we discovered a minimal myostatin inhibitor 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) derived from positions 21-43 of the mouse myostatin prodomain. We previously identified key residues (N-terminal Trp(21), rodent-specific Tyr(27), and all aliphatic amino acids) required for effective inhibition through structure-activity relationship (SAR) studies based on 1 and characterized a 3-fold more potent inhibitor 2 bearing a 2-naphthyloxyacetyl group at position 21...
July 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28725008/methylglyoxal-and-advanced-glycation-end-products-insight-of-the-regulatory-machinery-affecting-the-myogenic-program-and-of-its-modulation-by-natural-compounds
#5
Mohammad Hassan Baig, Arif Tasleem Jan, Gulam Rabbani, Khurshid Ahmad, Jalaluddin M Ashraf, Taeyeon Kim, Han Sol Min, Yong Ho Lee, Won-Kyung Cho, Jin Yeul Ma, Eun Ju Lee, Inho Choi
Methylglyoxal (MG) is a reactive dicarbonyl intermediate and a precursor of advanced glycation end products (AGEs). The authors investigated the role played by AGEs in muscle myopathy and the amelioration of its effects by curcumin and gingerol. In addition to producing phenotypical changes, MG increased oxidative stress and reduced myotube formation in C2C12 cells. RAGE (receptor for AGEs) expression was up-regulated and MYOD and myogenin (MYOG) expressions were concomitantly down-regulated in MG-treated cells...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28723591/molecular-characterization-and-expression-analysis-of-the-myostatin-gene-and-its-association-with-growth-traits-in-noble-scallop-chlamys-nobilis
#6
Sigang Fan, Youhou Xu, Baosuo Liu, Wenyao He, Bo Zhang, Jiaqi Su, Dahui Yu
Myostatin (MSTN), also called growth and differentiation factor-8 (GDF-8), is a member of the transforming growth factor-β (TGF-β) superfamily and an inhibitor of muscle differentiation and growth. In this report, we identified and characterized a MSTN gene (CnMSTN) from the scallop Chlamys nobilis. The open reading frame of CnMSTN was 1374bp in length, encoding 457 amino acids. The structure of CnMSTN included a putative signal peptide, a TGF-β propeptide domain, and a conserved TGF-β domain. Phylogenetic analysis showed that the CnMSTN gene was clustered in the same subgroup with the MSTN gene found in Mollusca...
July 16, 2017: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
https://www.readbyqxmd.com/read/28691106/recombinant-myostatin-reduces-highly-expressed-micrornas-in-differentiating-c2c12-cells
#7
Zachary A Graham, Rita De Gasperi, William A Bauman, Christopher P Cardozo
Myostatin is small glycopeptide that is produced and secreted by skeletal muscle. It is a potent negative regulator of muscle growth that has been associated with conditions of frailty. In C2C12 cells, myostatin limits cell differentiation. Myostatin acts through activin receptor IIB, activin receptor-like kinase (ALK) and Smad transcription factors. microRNAs (miRNA) are short, 22 base pair nucleotides that bind to the 3' UTR of target mRNA to repress translation or reduce mRNA stability. In the present study, expression in differentiating C2C12 cells of the myomiRs miR-1 and 133a were down-regulated following treatment with 1 μg of recombinant myostatin at 1 d post-induction of differentiation while all myomiRs (miR-1, 133a/b and 206) were upregulated by SB431542, a potent ALK4/5/7 inhibitor which reduces Smad2 signaling, at 1 d and all, with the exception of miR-206, were upregulated by SB431542 at 3 d...
March 2017: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/28666853/recombinant-bovine-growth-hormone-rbgh-enhances-somatic-growth-by-regulating-the-gh-igf-axis-in-fingerlings-of-gilthead-sea-bream-sparus-aurata
#8
Emilio J Vélez, Miquel Perelló, Sheida Azizi, Alberto Moya, Esmail Lutfi, Jaume Pérez-Sánchez, Josep A Calduch-Giner, Isabel Navarro, Josefina Blasco, Jaume Fernández-Borràs, Encarnación Capilla, Joaquim Gutiérrez
The growth hormone (GH)/insulin-like growth factors (IGFs) endocrine axis is the main growth-regulator system in vertebrates. Some authors have demonstrated the positive effects on growth of a sustained-release formulation of a recombinant bovine GH (rBGH) in different fish species. The aim of this work was to characterize the effects of a single injection of rBGH in fingerlings of gilthead sea bream on growth, GH-IGF axis, and both myogenic and osteogenic processes. Thus, body weight and specific growth rate were significantly increased in rBGH-treated fish respect to control fish at 6weeks post-injection, whereas the hepatosomatic index was decreased and the condition factor and mesenteric fat index were unchanged, altogether indicating enhanced somatic growth...
June 27, 2017: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28608457/potential-therapeutic-interventions-for-chronic-kidney-disease-associated-sarcopenia-via-indoxyl-sulfate-induced-mitochondrial-dysfunction
#9
Yuki Enoki, Hiroshi Watanabe, Riho Arake, Rui Fujimura, Kana Ishiodori, Tadashi Imafuku, Kento Nishida, Ryusei Sugimoto, Saori Nagao, Shigeyuki Miyamura, Yu Ishima, Motoko Tanaka, Kazutaka Matsushita, Hirotaka Komaba, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama
BACKGROUND: Chronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS-targeted intervention using AST-120, which inhibits IS accumulation, or mitochondria-targeted intervention using L-carnitine or teneligliptin, a dipeptidyl peptidase-4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice...
June 12, 2017: Journal of Cachexia, Sarcopenia and Muscle
https://www.readbyqxmd.com/read/28607086/specific-targeting-of-tgf-%C3%AE-family-ligands-demonstrates-distinct-roles-in-the-regulation-of-muscle-mass-in-health-and-disease
#10
Justin L Chen, Kelly L Walton, Adam Hagg, Timothy D Colgan, Katharine Johnson, Hongwei Qian, Paul Gregorevic, Craig A Harrison
The transforming growth factor-β (TGF-β) network of ligands and intracellular signaling proteins is a subject of intense interest within the field of skeletal muscle biology. To define the relative contribution of endogenous TGF-β proteins to the negative regulation of muscle mass via their activation of the Smad2/3 signaling axis, we used local injection of adeno-associated viral vectors (AAVs) encoding ligand-specific antagonists into the tibialis anterior (TA) muscles of C57BL/6 mice. Eight weeks after AAV injection, inhibition of activin A and activin B signaling produced moderate (∼20%), but significant, increases in TA mass, indicating that endogenous activins repress muscle growth...
June 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28539643/myostatin-a-profibrotic-factor-and-the-main-inhibitor-of-striated-muscle-mass-is-present-in-the-penile-and-vascular-smooth-muscle
#11
I Kovanecz, M Masouminia, R Gelfand, D Vernet, J Rajfer, N F Gonzalez-Cadavid
Myostatin is present in striated myofibers but, except for myometrial cells, has not been reported within smooth muscle cells (SMC). We investigated in the rat whether myostatin is present in SMC within the penis and the vascular wall and, if so, whether it is transcriptionally expressed and associated with the loss of corporal SMC occurring in certain forms of erectile dysfunction (ED). Myostatin protein was detected by immunohistochemistry/fluorescence and western blots in the perineal striated muscles, and also in the SMC of the penile corpora, arteries and veins, and aorta...
May 25, 2017: International Journal of Impotence Research
https://www.readbyqxmd.com/read/28533206/myostatin-like-proteins-regulate-synaptic-function-and-neuronal-morphology
#12
Hrvoje Augustin, Kieran McGourty, Joern R Steinert, Helena M Cochemé, Jennifer Adcott, Melissa Cabecinha, Alec Vincent, Els F Halff, Josef T Kittler, Emmanuel Boucrot, Linda Partridge
Growth factors of the TGF-β superfamily play key roles in regulating neuronal and muscle function. Myostatin (or GDF8) and GDF11 are potent negative regulators of skeletal muscle mass. However, expression of both Myostatin and its cognate receptors in other tissues, including brain and peripheral nerves, suggests a potential wider biological role. Here, we show that Myoglianin (MYO), the Drosophila homolog of Myostatin and GDF11, regulates not only body weight and muscle size, but also inhibits neuromuscular synapse strength and composition in a Smad2-dependent manner...
May 22, 2017: Development
https://www.readbyqxmd.com/read/28471505/role-of-follistatin-in-muscle-and-bone-alterations-induced-by-gravity-change-in-mice
#13
Naoyuki Kawao, Hironobu Morita, Koji Obata, Kohei Tatsumi, Hiroshi Kaji
Interactions between muscle and bone have been recently noted. We reported that the vestibular system plays crucial roles in the changes in muscle and bone induced by hypergravity in mice. However, the details of the mechanisms by which gravity change affects muscle and bone through the vestibular system still remain unknown. Here, we investigated the roles of humoral factors linking muscle to bone and myostatin-related factors in the hypergravity-induced changes in muscle and bone in mice with vestibular lesions (VL)...
May 4, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28406165/myostatin-mediates-abdominal-aortic-atherosclerosis-progression-by-inducing-vascular-smooth-muscle-cell-dysfunction-and-monocyte-recruitment
#14
D Verzola, S Milanesi, M Bertolotto, S Garibaldi, B Villaggio, C Brunelli, M Balbi, P Ameri, F Montecucco, D Palombo, G Ghigliotti, G Garibotto, J H Lindeman, C Barisione
Myostatin (Mstn) is a skeletal muscle growth inhibitor involved in metabolic disorders and heart fibrosis. In this study we sought to verify whether Mstn is also operative in atherosclerosis of abdominal aorta. In human specimens, Mstn expression was almost absent in normal vessels, became detectable in the media of non-progressive lesions and increased with the severity of the damage. In progressive atherosclerotic lesions, Mstn was present in the media, neointima, plaque shoulder and in infiltrating macrophages...
April 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28396837/myostatin-promotes-tenogenic-differentiation-of-c2c12-myoblast-cells-through-smad3
#15
Kazutaka Uemura, Masanori Hayashi, Toshiro Itsubo, Ayumu Oishi, Hiroko Iwakawa, Masatoshi Komatsu, Shigeharu Uchiyama, Hiroyuki Kato
Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, is expressed in developing and adult skeletal muscle and negatively regulates skeletal muscle growth. Recently, myostatin has been found to be expressed in tendons and increases tendon fibroblast proliferation and the expression of tenocyte markers. C2C12 is a mouse myoblast cell line, which has the ability to transdifferentiate into osteoblast and adipocyte lineages. We hypothesized that myostatin is capable of inducing tenogenic differentiation of C2C12 cells...
April 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28277951/within-winter-flexibility-in-muscle-masses-myostatin-and-cellular-aerobic-metabolic-intensity-in-passerine-birds
#16
David L Swanson, Marisa O King, William Culver, Yufeng Zhang
Metabolic rates of passerine birds are flexible traits that vary both seasonally and among and within winters. Seasonal variation in summit metabolic rates (Msum = maximum thermoregulatory metabolism) in birds is consistently correlated with changes in pectoralis muscle and heart masses and sometimes with variation in cellular aerobic metabolic intensity, so these traits might also be associated with shorter-term, within-winter variation in metabolic rates. To determine whether these mechanisms are associated with within-winter variation in Msum, we examined the effects of short-term (ST; 0-7 d), medium-term (MT; 14-30 d), and long-term (LT; 30-yr means) temperature variables on pectoralis muscle and heart masses, pectoralis expression of the muscle-growth inhibitor myostatin and its metalloproteinase activators TLL-1 and TLL-2, and pectoralis and heart citrate synthase (CS; an indicator of cellular aerobic metabolic intensity) activities for two temperate-zone resident passerines, house sparrows (Passer domesticus) and dark-eyed juncos (Junco hyemalis)...
March 2017: Physiological and Biochemical Zoology: PBZ
https://www.readbyqxmd.com/read/28247316/selecting-potential-pharmacological-interventions-in-sarcopenia
#17
REVIEW
Amanda J Kilsby, Avan A Sayer, Miles D Witham
Sarcopenia of age is prevalent and costly and proven pharmacological interventions are currently lacking. The pathophysiology of sarcopenia is incompletely understood but appears to involve multiple pathways, including inflammation, hormonal dysregulation, impaired regeneration, mitochondrial dysfunction and denervation. There are several ways in which we might select potential pharmacological interventions for testing in clinical trials. These include a 'bottom-up' approach using basic science to elucidate the molecular processes involved and identify potential targets from this knowledge-a strategy that has led to the development of myostatin inhibitors...
April 2017: Drugs & Aging
https://www.readbyqxmd.com/read/28217409/muscle-derived-stem-cells-stimulate-muscle-myofiber-repair-and-counteract-fat-infiltration-in-a-diabetic-mouse-model-of-critical-limb-ischemia
#18
J Tsao, I Kovanecz, N Awadalla, R Gelfand, I Sinha-Hikim, R A White, N F Gonzalez-Cadavid
BACKGROUND: Critical Limb Ischemia (CLI) affects patients with Type 2 Diabetes (T2D) and obesity, with high risk of amputation and post-surgical mortality, and no effective medical treatment. Stem cell therapy, mainly with bone marrow mesenchymal, adipose derived, endothelial, hematopoietic, and umbilical cord stem cells, is promising in CLI mouse and rat models and is in clinical trials. Their general focus is on angiogenic repair, with no reports on the alleviation of necrosis, lipofibrosis, and myofiber regeneration in the ischemic muscle, or the use of Muscle Derived Stem Cells (MDSC) alone or in combination with pharmacological adjuvants, in the context of CLI in T2D...
December 2016: Journal of Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28122601/inhibition-of-stat3-signaling-ameliorates-atrophy-of-the-soleus-muscles-in-mice-lacking-the-vitamin-d-receptor
#19
Suchitra D Gopinath
BACKGROUND: Although skeletal muscle wasting has long been observed as a clinical outcome of impaired vitamin D signaling, precise molecular mechanisms that mediate the loss of muscle mass in the absence of vitamin D signaling are less clear. To determine the molecular consequences of vitamin D signaling, we analyzed the role of signal transducer and activator of transcription 3 (Stat3) signaling, a known contributor to various muscle wasting pathologies, in skeletal muscles. METHODS: We isolated soleus (slow) and tibialis anterior (fast) muscles from mice lacking the vitamin D receptor (VDR(-/-)) and used western blot analysis, quantitative RTPCR, and pharmacological intervention to analyze muscle atrophy in VDR(-/-) mice...
January 25, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28105285/structural-basis-for-the-effective-myostatin-inhibition-of-the-mouse-myostatin-prodomain-derived-minimum-peptide
#20
Tomo Asari, Kentaro Takayama, Akari Nakamura, Takahiro Shimada, Akihiro Taguchi, Yoshio Hayashi
Myostatin inhibition is one of the promising strategies for treating muscle atrophic disorders, including muscular dystrophy. It is well-known that the myostatin prodomain derived from the myostatin precursor acts as an inhibitor of mature myostatin. In our previous study, myostatin inhibitory minimum peptide 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) was discovered from the mouse myostatin prodomain. In the present study, alanine scanning of 1 demonstrated that the key amino acid residues for the effective inhibitory activity are rodent-specific Tyr and C-terminal aliphatic residues, in addition to N-terminal Trp residue...
January 12, 2017: ACS Medicinal Chemistry Letters
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