Myostatin/activin pathway antagonism: molecular basis and therapeutic potential.
01 Oct 2013-The International Journal of Biochemistry & Cell Biology (Int J Biochem Cell Biol)-Vol. 45, Iss: 10, pp 2333-2347
TL;DR: Pharmacological blockade of the myostatin/activin-ActRIIB pathway has been shown to prevent or reverse the loss of muscle mass and strength in various disease models including cancer cachexia and renal failure and can markedly prolong the lifespan of animals with cancer-associated muscle loss.
About: This article is published in The International Journal of Biochemistry & Cell Biology.The article was published on 2013-10-01. It has received 244 citations till now. The article focuses on the topics: Myostatin & Activin type 2 receptors.
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TL;DR: Major advances in the understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting.
Abstract: Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer-associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting.
741 citations
TL;DR: Myostatin inhibition could yield new therapeutic directions for blocking muscle protein wasting in CKD or disorders associated with its complications, suggesting that therapeutic strategies will be developed to suppress or block protein loss.
Abstract: Muscle atrophy frequently complicates the course of chronic kidney disease (CKD) and is associated with excess morbidity and mortality. In this Review, the authors describe how CKD stimulates catabolic pathways that interfere with cellular protein metabolism and discuss how knowledge of these pathways might enable the development of therapies to block muscle wasting in catabolic conditions.
428 citations
TL;DR: Using proteins with low ammoniagenic potential, leucine enriched amino acid supplementation, long-term ammonia lowering strategies and a combination of resistance and endurance exercise to increase muscle mass and function may target the molecular abnormalities in the muscle.
408 citations
Cites background from "Myostatin/activin pathway antagonis..."
...Novel molecular targeted strategies Myostatin antagonists[91], direct mTORC1 activators[66, 133], antioxidants, and mitochondrial protective agents have the potential to benefit skeletal muscle protein turnover but have not been adequately evaluated....
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...Myostatin is a known inhibitor of protein synthesis and potentially activates the ubiquitin proteasome and autophagy mediated proteolysis[21, 22, 91]....
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TL;DR: A novel, human anti-ActRII antibody is developed to prevent binding of ligands to the receptors and thus inhibit downstream signaling in the myostatin/activin type II receptor pathway, highlighting the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings.
Abstract: 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. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings.
280 citations
Cites background from "Myostatin/activin pathway antagonis..."
...Phosphorylated Smad2/3 are then translocated to the nucleus and modulate the transcription of target genes, including MyoD (4, 16)....
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...Extensive studies have documented the key role of myostatin as a negative regulator of skeletal muscle mass, acting primarily via the activin type IIB receptor (ActRIIB) (4)....
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References
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TL;DR: Results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth, which is significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass.
Abstract: The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of growth and differentiation factors playing important roles in regulating embryonic development and in maintaining tissue homeostasis in adult animals. Using degenerate polymerase chain reaction, we have identified a new murine TGF-beta family member, growth/differentiation factor-8 (GDF-8), which is expressed specifically in developing and adult skeletal muscle. During early stages of embryogenesis, GDF-8 expression is restricted to the myotome compartment of developing somites. At later stages and in adult animals, GDF-8 is expressed in many different muscles throughout the body. To determine the biological function of GDF-8, we disrupted the GDF-8 gene by gene targeting in mice. GDF-8 null animals are significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weigh 2-3 times more than those of wild-type animals, and the increase in mass appears to result from a combination of muscle cell hyperplasia and hypertrophy. These results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth.
3,791 citations
Edinburgh Royal Infirmary1, University of St. Gallen2, Charité3, Sahlgrenska University Hospital4, University of Texas MD Anderson Cancer Center5, University of Alberta6, Mayo Clinic7, McGill University8, University of Cagliari9, Cleveland Clinic10, Sapienza University of Rome11, Nottingham University Hospitals NHS Trust12
TL;DR: A framework exists on a framework for the definition and classification of cancer cachexia, a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment.
Abstract: Summary To develop a framework for the definition and classification of cancer cachexia a panel of experts participated in a formal consensus process, including focus groups and two Delphi rounds. Cancer cachexia was defined as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height (body-mass index [BMI] 2 ) or skeletal muscle mass (sarcopenia). An agreement was made that the cachexia syndrome can develop progressively through various stages—precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Consensus exists on a framework for the definition and classification of cancer cachexia. After validation, this should aid clinical trial design, development of practice guidelines, and, eventually, routine clinical management.
3,548 citations
TL;DR: In the course of an electron microscopic study of the peripheral region of the skeletal muscle fiber of the frog, the presence of certain cells, intimately associated with the muscle fiber, have been observed which the authors have chosen to call satellite cells.
Abstract: In the course of an electron microscopic study of the peripheral region of the skeletal muscle fiber of the frog, the presence of certain cells, intimately associated with the muscle fiber, have been observed which we have chosen to call satellite cells. Since these cells have not been reported previously and indeed might be of interest to students of muscle histology and furthermore, as we shall suggest, might be pertinent to the vexing problem of skeletal muscle regeneration, a brief communication describing this finding is warranted prior to a more detailed study. The observations reported here have been made on bundles of fibers dissected from the tibialis anticus muscle of the frog. The material has been fixed by the conventional method with osmium tetroxide, and the embedding has been carried out with methacrylate and with epoxy (epon) resin. In sections that were \"stained,\" the lead hydroxide solution of Watson (1) was used. As seen in the attached electron micrograph of the satellite cell, the striking paucity of cytoplasm relative to its nucleus results in the cell assuming the shape of the nucleus. In fact, it is virtually impossible to discern the cellular nature of this entity in the light microscope, as it appears to be indistinguishable from a peripheral muscle nucleus proper. In electron micrographs the cell is seen \"wedged\" between the plasma membrane of the muscle fiber and the basement membrane, which invests the fiber throughout its length in close association with the plasma membrane. The intimacy of this satellite cell with respect to the multinucleate muscle cell is further revealed in the fact that, in general, the surface of the muscle fiber is not distorted outward but instead the satellite cell protrudes inward pushing the myofibrils of the muscle cell aside. On the inner surface, the plasma membrane of the satellite cell is in appositon with the plasma membrane of the muscle cell. Unfortunately, because of the limited observations and the difficulty in acquiring sufficient data readily with electron micrographic techniques, it is not possible at present to estimate the frequency of occurrence of these cells in a typical muscle fiber in our preparation of tibialis anticus muscle. The only generalization warranted at this time is that the peripheral muscle nuclei proper occur much more frequently than the satellite cells. It is interesting that upon alerting other investigators to these findings, similar cells have been found in electron micrographs of two other muscles of the frog, namely sartorius (2) and ileofibularis (3), and of the sartorius and tongue muscle of the white rat (4). (Though the direct evidence is restricted to these two vertebrates, it seems reasonable to hazard a guess that skeletal muscle fibers of vertebrates in general contain satellite cells.) It is tempting to speculate about the origin and the role of the satellite cells. Before stating the several possible hypotheses that have figured in our interpretations, it is pertinent to recall a most striking characteristic of regenerating muscle fibers in the least ambiguous case where the sarcolemma-tube remains intact, the myoplasm having undergone hyaline formation and retraction as a result of trauma. Within 48 hours a marked presence of \"free cells\" is noted in the empty tube, the cells appearing both as \"round\" and \" f u s i f o r m \" types (5). Moreover, in tissue culture studies of mature skeletal muscle explants, fi'ee cells are also seen emanating from the explant. The central question must be asked: what is the origin of these cells? Most cytologists lean toward the interpretation that surviving nuclei in the damaged multinucleate muscle cell give rise to single cells by \"gathering up\" cytoplasm from the sarcoplasm of the muscle cell--an unusual mechanism, however, for vertebrate systems. If this point of view is taken, the first and immediate hypothesis suggests itself, namely, that in the resting state some cells are being produced at a slow rate by the above mechanism and reside just outside the plasma membrane of the muscle cell, and that upon being stimulated by trauma, e.g. ischemia, mechanical compression, toxic agents, etc., the rate of production of such cells is increased. The second hypothesis, more in keeping with conventional notions of cytology, is that the satellite cells are remnants from the embryonic development of the multinucleate muscle cell which results from the process of fusion of individual myoblasts. Thus the satellite cells are
3,364 citations
TL;DR: Two genes encode ubiquitin ligases that are potential drug targets for the treatment of muscle atrophy, and mice deficient in either MAFbx orMuRF1 were found to be resistant to atrophy.
Abstract: Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.
3,174 citations
"Myostatin/activin pathway antagonis..." refers background in this paper
...Cohen S, Brault JJ, Gygi SP, Glass DJ, Valenzuela DM, Gartner C, et al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1dependent ubiquitylation....
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...Degradation of key regulatory proteins by Atrogin-1/MAFbx is primarily important in inhibiting protein synthesis during atrophy (Lagirand-Cantaloube et al., 2008) but may have other roles (Lokireddy et al., 2012a,b), while MuRF1 is of special importance in atrophying muscle because it catalyzes the most of the increased polyubiquitination of major muscle proteins, especially components of the thick filaments (Cohen et al., 2009, 2012), which leads to their rapid degradation by the 26S proteasome....
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...IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1....
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...The increase in UPS activity as seen in catabolic states depends on transcriptional activation of the muscle-specific ubiquitin ligases, Atrogin-1/MAFbx (Gomes et al., 2001), and MuRF1 (Bodine et al., 2001; Koyama et al., 2008; Cohen et al., 2009; Polge et al., 2011), as well as ubiquitin and proteasome subunits (Lecker et al., 2006; Mitch and Goldberg, 1996)....
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...Recent evidence demonstrates that in animal models of wasting diseases, increased myostatin/activin-Smad signaling inhibits Akt activity in muscle, increases FoxO activity and upregulates critical atrogenes (e.g. Atrogin-1/MAFbx and MuRF1)....
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TL;DR: It is shown that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction.
2,657 citations