Myostatin/activin pathway antagonism: Molecular basis and therapeutic potential

H.Q. Han1, Xiaolan Zhou1, William E. Mitch2, Alfred L. Goldberg3
1Metabolic Disorders Department, Amgen, Thousand Oaks, CA, USA
2Nephrology Division, Baylor College of Medicine, Houston, TX, USA
3Department of Cell Biology, Harvard Medical School, Boston, MA, USA

Tài liệu tham khảo

Acharyya, 2004, Cancer cachexia is regulated by selective targeting of skeletal muscle gene products, Journal of Clinical Investigation, 114, 370, 10.1172/JCI200420174 Akhurst, 2012, Targeting the TGFbeta signalling pathway in disease, Nature Reviews Drug Discovery, 11, 790, 10.1038/nrd3810 Akpan, 2009, The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity, International Journal of Obesity (London), 33, 1265, 10.1038/ijo.2009.162 Allen, 2009, Effects of spaceflight on murine skeletal muscle gene expression, Journal of Applied Physiology, 106, 582, 10.1152/japplphysiol.90780.2008 Anderson, 2008, Identification of a novel pool of extracellular pro-myostatin in skeletal muscle, Journal of Biological Chemistry, 283, 7027, 10.1074/jbc.M706678200 Anker, 1997, Wasting as independent risk factor for mortality in chronic heart failure, Lancet, 349, 1050, 10.1016/S0140-6736(96)07015-8 Anker, 2004, Cardiac cachexia, Annals of Medicine, 36, 518, 10.1080/07853890410017467 Annes, 2003, Making sense of latent TGFbeta activation, Journal of Cell Science, 116, 217, 10.1242/jcs.00229 Argiles, 1992, The role of cytokines in muscle wasting: its relation with cancer cachexia, Medicinal Research Reviews, 12, 637, 10.1002/med.2610120605 Attaix, 2005, The ubiquitin–proteasome system and skeletal muscle wasting, Essays in Biochemistry, 41, 173, 10.1042/EB0410173 Attaix, 2008, Role of the ubiquitin–proteasome pathway in muscle atrophy in cachexia, Current Opinion in Supportive and Palliative Care, 2, 262, 10.1097/SPC.0b013e3283196ac2 Aversa, 2012, Changes in myostatin signaling in non-weight-losing cancer patients, Annals of Surgical Oncology, 19, 1350, 10.1245/s10434-011-1720-5 Baccarelli, 2001, Activin A serum levels and aging of the pituitary–gonadal axis: a cross-sectional study in middle-aged and elderly healthy subjects, Experimental Gerontology, 36, 1403, 10.1016/S0531-5565(01)00117-6 Bamberger, 2005, Activin controls skin morphogenesis and wound repair predominantly via stromal cells and in a concentration-dependent manner via keratinocytes, American Journal of Pathology, 167, 733, 10.1016/S0002-9440(10)62047-0 Bailey, 2006, Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy, Journal of the American Society of Nephrology, 17, 1388, 10.1681/ASN.2004100842 Bailey, 1996, The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent, ubiquitin–proteasome pathway, Journal of Clinical Investigation, 97, 1447, 10.1172/JCI118566 Bechet, 2005, Lysosomal proteolysis in skeletal muscle, International Journal of Biochemistry and Cell Biology, 37, 2098, 10.1016/j.biocel.2005.02.029 Benny Klimek, 2010, Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia, Biochemical and Biophysical Research Communications, 391, 1548, 10.1016/j.bbrc.2009.12.123 Bernardo, 2010, Postnatal PPARdelta activation and myostatin inhibition exert distinct yet complimentary effects on the metabolic profile of obese insulin-resistant mice, PLoS ONE, 5, e11307, 10.1371/journal.pone.0011307 Bilezikjian, 2004, Autocrine/paracrine regulation of pituitary function by activin, inhibin and follistatin, Molecular and Cellular Endocrinology, 225, 29, 10.1016/j.mce.2004.02.010 Bilezikjian, 2006, Pituitary actions of ligands of the TGF-beta family: activins and inhibins, Reproduction, 132, 207, 10.1530/rep.1.01073 Bilezikjian, 1993, Activin-A regulates follistatin secretion from cultured rat anterior pituitary cells, Endocrinology, 133, 2554, 10.1210/endo.133.6.8243277 Bilezikjian, 2011, The local control of the pituitary by activin signaling and modulation, Open Neuroendocrinology Journal, 4, 90, 10.2174/1876528901104010090 Binns, 2010, Identification of the myostatin locus (MSTN) as having a major effect on optimum racing distance in the Thoroughbred horse in the USA, Animal Genetics, 41, 154, 10.1111/j.1365-2052.2010.02126.x Blumenfeld, 2001, Inhibin, activin, and follistatin in human fetal pituitary and gonadal physiology, Annals of the New York Academy of Sciences, 943, 34, 10.1111/j.1749-6632.2001.tb03788.x Bo Li, 2012, Inhibition of myostatin reverses muscle fibrosis through apoptosis, Journal of Cell Science, 125, 3957, 10.1242/jcs.090365 Bodine, 2001, Identification of ubiquitin ligases required for skeletal muscle atrophy, Science, 294, 1704, 10.1126/science.1065874 Bogdanovich, 2002, Functional improvement of dystrophic muscle by myostatin blockade, Nature, 420, 418, 10.1038/nature01154 Bogdanovich, 2005, Myostatin propeptide-mediated amelioration of dystrophic pathophysiology, FASEB Journal, 19, 543, 10.1096/fj.04-2796com Bonanni, 2011, Protein-energy wasting and mortality in chronic kidney disease, International Journal of Environmental Research and Public Health, 8, 1631, 10.3390/ijerph8051631 Bower, 2012, The genetic origin and history of speed in the Thoroughbred racehorse, Nature Communications, 3, 643, 10.1038/ncomms1644 Brault, 2010, Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy, Journal of Biological Chemistry, 285, 19460, 10.1074/jbc.M110.113092 Breitbart, 2011, Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting, American Journal of Physiology-Heart and Circulatory Physiology, 300, H1973, 10.1152/ajpheart.00200.2011 Busquets, 2012, Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance, The Journal of Cachexia, Sarcopenia and Muscle, 3, 37, 10.1007/s13539-011-0049-z Carlson, 1999, Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading, American Journal of Physiology, 277, R601 Chang, 2010, Overexpression of activin A in oral squamous cell carcinoma: association with poor prognosis and tumor progression, Annals of Surgical Oncology, 17, 1945, 10.1245/s10434-010-0926-2 Chang, 1978, The metabolic fates of amino acids and the formation of glutamine in skeletal muscle, Journal of Biological Chemistry, 253, 3685, 10.1016/S0021-9258(17)34855-X Choi, 2008, Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism, Proceedings of the National Academy of Sciences of the United States of America, 105, 19926, 10.1073/pnas.0810339105 Clop, 2006, A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep, Nature Genetics, 38, 813, 10.1038/ng1810 Clotman, 2006, Control of hepatic differentiation by activin/TGFbeta signaling, Cell Cycle, 5, 168, 10.4161/cc.5.2.2341 Coats, 2002, Origin of symptoms in patients with cachexia with special reference to weakness and shortness of breath, International Journal of Cardiology, 85, 133, 10.1016/S0167-5273(02)00242-5 Cobellis, 2004, High concentrations of activin A in the peritoneal fluid of women with epithelial ovarian cancer, Journal of the Society for Gynecologic Investigation, 11, 203, 10.1016/j.jsgi.2003.10.008 Cohen, 2009, During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation, Journal of Cell Biology, 185, 1083, 10.1083/jcb.200901052 Cohen, 2012, Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy, Journal of Cell Biology, 198, 575, 10.1083/jcb.201110067 Costelli, 2008, Muscle myostatin signalling is enhanced in experimental cancer cachexia, European Journal of Clinical Investigation, 38, 531, 10.1111/j.1365-2362.2008.01970.x D’Antona, 2000, Increased maternal serum activin A but not follistatin levels in pregnant women with hypertensive disorders, Journal of Endocrinology, 165, 157, 10.1677/joe.0.1650157 Dhawan, 2005, Stem cells in postnatal myogenesis: molecular mechanisms of satellite cell quiescence, activation and replenishment, Trends in Cell Biology, 15, 666, 10.1016/j.tcb.2005.10.007 Doherty, 2003, Invited review: aging and sarcopenia, Journal of Applied Physiology, 95, 1717, 10.1152/japplphysiol.00347.2003 Du, 2004, Activation of caspase 3 is an initial step triggering muscle proteolysis in catabolic conditions, Journal of Clinical Investigation, 113, 115, 10.1172/JCI18330 Evans, 2010, Skeletal muscle loss: cachexia, sarcopenia, and inactivity, American Journal of Clinical Nutrition, 91, 1123S, 10.3945/ajcn.2010.28608A Evans, 2008, Cachexia: a new definition, Clinical Nutrition, 27, 793, 10.1016/j.clnu.2008.06.013 Fearon, 2011, Definition and classification of cancer cachexia: an international consensus, Lancet Oncology, 12, 489, 10.1016/S1470-2045(10)70218-7 Fearon, 2013, Understanding the mechanisms and treatment options in cancer cachexia, Nature Reviews Clinical Oncology, 10, 90, 10.1038/nrclinonc.2012.209 Fielding, 2011, Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia, Journal of the American Medical Directors Association, 12, 249, 10.1016/j.jamda.2011.01.003 Fouque, 2008, A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease, Kidney International, 73, 391, 10.1038/sj.ki.5002585 Fournier, 2012, Blockade of the activin receptor IIb activates functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism, Molecular and Cellular Biology, 32, 2871, 10.1128/MCB.06575-11 George Carlson, 2011, Soluble activin receptor type IIB increases forward pulling tension in the mdx mouse, Muscle and Nerve, 43, 694, 10.1002/mus.21944 George, 2010, Myostatin activation in patients with advanced heart failure and after mechanical unloading, European Journal of Heart Failure, 12, 444, 10.1093/eurjhf/hfq039 Glass, 2005, Skeletal muscle hypertrophy and atrophy signaling pathways, International Journal of Biochemistry and Cell Biology, 37, 1974, 10.1016/j.biocel.2005.04.018 Glass, 2010, Signaling pathways perturbing muscle mass, Current Opinion in Clinical Nutrition and Metabolic Care, 13, 225, 10.1097/MCO.0b013e32833862df Goldberg, 1969, Relationship between cortisone and muscle work in determining muscle size, Journal of Physiology, 200, 667, 10.1113/jphysiol.1969.sp008715 Gomes, 2001, Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy, Proceedings of the National Academy of Sciences of the United States of America, 98, 14440, 10.1073/pnas.251541198 Gonzalez-Cadavid, 1998, Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting, Proceedings of the National Academy of Sciences of the United States of America, 95, 14938, 10.1073/pnas.95.25.14938 Gray, 2001, Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan-glycan, Molecular and Cellular Endocrinology, 180, 47, 10.1016/S0303-7207(01)00515-9 Griffiths, 1996, Muscle mass, survival, and the elderly ICU patient, Nutrition, 12, 456, 10.1016/S0899-9007(96)00141-4 Gruson, 2011, Increased plasma myostatin in heart failure, European Journal of Heart Failure, 13, 734, 10.1093/eurjhf/hfr024 Hamrick, 2010, Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury, Journal of Trauma, 69, 579, 10.1097/TA.0b013e3181c451f4 Han, 2011, Targeting the myostatin signaling pathway to treat muscle wasting diseases, Current Opinion in Supportive and Palliative Care, 5, 334, 10.1097/SPC.0b013e32834bddf9 Harada, 1996, Serum immunoreactive activin A levels in normal subjects and patients with various diseases, Journal of Clinical Endocrinology and Metabolism, 81, 2125 Heineke, 2010, Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure, Circulation, 121, 419, 10.1161/CIRCULATIONAHA.109.882068 Hellerstein, 1950, Atrophy of the heart; a correlative study of 85 proved cases, Circulation, 1, 93, 10.1161/01.CIR.1.1.93 Hemmati-Brivanlou, 1994, Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity, Cell, 77, 283, 10.1016/0092-8674(94)90320-4 Hofland, 2012, Activin A stimulates AKR1C3 expression and growth in human prostate cancer, Endocrinology, 153, 5726, 10.1210/en.2011-2065 Holzbaur, 2006, Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis, Neurobiology of Disease, 23, 697, 10.1016/j.nbd.2006.05.009 Honors, 2012, The role of insulin resistance in the development of muscle wasting during cancer cachexia, The Journal of Cachexia, Sarcopenia and Muscle, 3, 5, 10.1007/s13539-011-0051-5 Hsieh-Li, 2000, A mouse model for spinal muscular atrophy, Nature Genetics, 24, 66, 10.1038/71709 Hu, 2009, Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice, Journal of Clinical Investigation, 119, 3059 Huang, 2010, Both low muscle mass and low fat are associated with higher all-cause mortality in hemodialysis patients, Kidney International, 77, 624, 10.1038/ki.2009.524 Hubner, 1999, Activin: a novel player in tissue repair processes, Histology and Histopathology, 14, 295 Hubner, 1997, Activin A: a novel player and inflammatory marker in inflammatory bowel disease?, Laboratory Investigation, 77, 311 Iannuzzi-Sucich, 2002, Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women, Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 57, M772, 10.1093/gerona/57.12.M772 Inagaki, 1974, Proceedings: causes of death in cancer patients, Cancer, 33, 568, 10.1002/1097-0142(197402)33:2<568::AID-CNCR2820330236>3.0.CO;2-2 Janssen, 2004, The healthcare costs of sarcopenia in the United States, Journal of the American Geriatrics Society, 52, 80, 10.1111/j.1532-5415.2004.52014.x Jones, 2007, Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia, Proceedings of the National Academy of Sciences of the United States of America, 104, 16239, 10.1073/pnas.0705971104 Ju, 2012, Serum myostatin levels and skeletal muscle wasting in chronic obstructive pulmonary disease, Respiratory Medicine, 106, 102, 10.1016/j.rmed.2011.07.016 Kleeff, 1998, Concomitant over-expression of activin/inhibin beta subunits and their receptors in human pancreatic cancer, International Journal of Cancer, 77, 860, 10.1002/(SICI)1097-0215(19980911)77:6<860::AID-IJC11>3.0.CO;2-5 Koncarevic, 2010, A soluble activin receptor type IIb prevents the effects of androgen deprivation on body composition and bone health, Endocrinology, 151, 4289, 10.1210/en.2010-0134 Kovesdy, 2009, Outcome predictability of biomarkers of protein-energy wasting and inflammation in moderate and advanced chronic kidney disease, American Journal of Clinical Nutrition, 90, 407, 10.3945/ajcn.2008.27390 Koyama, 2008, Muscle RING-finger protein-1 (MuRF1) as a connector of muscle energy metabolism and protein synthesis, Journal of Molecular Biology, 376, 1224, 10.1016/j.jmb.2007.11.049 Kuang, 2008, Niche regulation of muscle satellite cell self-renewal and differentiation, Cell Stem Cell, 2, 22, 10.1016/j.stem.2007.12.012 Kudryashova, 2012, Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H, Journal of Clinical Investigation, 122, 1764, 10.1172/JCI59581 Kwak, 2004, Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3alpha-II during cancer cachexia, Cancer Research, 64, 8193, 10.1158/0008-5472.CAN-04-2102 Lagirand-Cantaloube, 2008, The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy, EMBO Journal, 27, 1266, 10.1038/emboj.2008.52 Lalani, 2000, Myostatin and insulin-like growth factor-I and -II expression in the muscle of rats exposed to the microgravity environment of the NeuroLab space shuttle flight, Journal of Endocrinology, 167, 417, 10.1677/joe.0.1670417 Lambert-Messerlian, 1999, Secretion of activin A in recurrent epithelial ovarian carcinoma, Gynecologic Oncology, 74, 93, 10.1006/gyno.1999.5417 Lang, 2001, Regulation of myostatin by glucocorticoids after thermal injury, FASEB Journal, 15, 1807, 10.1096/fj.00-0849fje Langley, 2002, Myostatin inhibits myoblast differentiation by down-regulating MyoD expression, Journal of Biological Chemistry, 277, 49831, 10.1074/jbc.M204291200 Larsen, 2011, Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation, American Journal of Physiology-Lung Cellular and Molecular Physiology, 301, L50, 10.1152/ajplung.00048.2010 Lawlor, 2011, Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice, American Journal of Pathology, 178, 784, 10.1016/j.ajpath.2010.10.035 LeBrasseur, 2009, Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice, Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 64, 940, 10.1093/gerona/glp068 Lecker, 2006, Protein degradation by the ubiquitin–proteasome pathway in normal and disease states, Journal of the American Society of Nephrology, 17, 1807, 10.1681/ASN.2006010083 Lecker, 2004, Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression, FASEB Journal, 18, 39, 10.1096/fj.03-0610com Lee, 2011, Myostatin induces autophagy in skeletal muscle in vitro, Biochemical and Biophysical Research Communications, 415, 632, 10.1016/j.bbrc.2011.10.124 Lee, 2012, Role of satellite cells versus myofibers in muscle hypertrophy induced by inhibition of the myostatin/activin signaling pathway, Proceedings of the National Academy of Sciences of the United States of America, 109, E2353, 10.1073/pnas.1206410109 Lee, 2001, Regulation of myostatin activity and muscle growth, Proceedings of the National Academy of Sciences of the United States of America, 98, 9306, 10.1073/pnas.151270098 Lee, 2004, Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin–proteasome systems by phosphatidylinositol 3 kinase, Journal of the American Society of Nephrology, 15, 1537, 10.1097/01.ASN.0000127211.86206.E1 Lenk, 2012, Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure, European Journal of Preventive Cardiology, 19, 404, 10.1177/1741826711402735 Lewis, 2000, Betaglycan binds inhibin and can mediate functional antagonism of activin signalling, Nature, 404, 411, 10.1038/35006129 Lokireddy, 2011, Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin–proteasome pathway-mediated loss of sarcomeric proteins, American Journal of Physiology-Cell Physiology, 301, C1316, 10.1152/ajpcell.00114.2011 Lokireddy, 2012, Identification of atrogin-1-targeted proteins during the myostatin-induced skeletal muscle wasting, American Journal of Physiology-Cell Physiology, 5, C512, 10.1152/ajpcell.00402.2011 Lokireddy, 2012, The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli, Cell Metabolism, 16, 613, 10.1016/j.cmet.2012.10.005 Luisi, 2001, Serum activin A levels in males and females during pubertal development, Gynecological Endocrinology, 15, 1, 10.1080/713602644 Ma, 2003, Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression, American Journal of Physiology-Endocrinology and Metabolism, 285, E363, 10.1152/ajpendo.00487.2002 Mak, 2012, An unusual appearance of renal epithelioid angiomyolipoma, Singapore Medical Journal, 53, e204 Mak, 2011, Wasting in chronic kidney disease, The Journal of Cachexia, Sarcopenia and Muscle, 2, 9, 10.1007/s13539-011-0019-5 Mammucari, 2007, FoxO3 controls autophagy in skeletal muscle in vivo, Cell Metabolism, 6, 458, 10.1016/j.cmet.2007.11.001 Mammucari, 2008, Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle, Autophagy, 4, 524, 10.4161/auto.5905 Massague, 2000, How cells read TGF-beta signals, Nature Reviews Molecular Cell Biology, 1, 169, 10.1038/35043051 Massague, 2012, TGFbeta signalling in context, Nature Reviews Molecular Cell Biology, 13, 616, 10.1038/nrm3434 Matzuk, 1994, Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice, Proceedings of the National Academy of Sciences of the United States of America, 91, 8817, 10.1073/pnas.91.19.8817 Mauro, 1961, Satellite cell of skeletal muscle fibers, Journal of Biophysical and Biochemical Cytology, 9, 493, 10.1083/jcb.9.2.493 May, 1986, Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism, Journal of Clinical Investigation, 77, 614, 10.1172/JCI112344 May, 1987, Mechanisms for defects in muscle protein metabolism in rats with chronic uremia: the influence of metabolic acidosis, Journal of Clinical Investigation, 79, 1099, 10.1172/JCI112924 Mayer, 2012, Activin A: a mediator governing inflammation, immunity, and repair, American Journal of Respiratory and Critical Care Medicine, 185, 350, 10.1164/rccm.201112-2210ED McCroskery, 2003, Myostatin negatively regulates satellite cell activation and self-renewal, Journal of Cell Biology, 162, 1135, 10.1083/jcb.200207056 McFarlane, 2008, Myostatin signals through Pax7 to regulate satellite cell self-renewal, Experimental Cell Research, 314, 317, 10.1016/j.yexcr.2007.09.012 McFarlane, 2011, Human myostatin negatively regulates human myoblast growth and differentiation, American Journal of Physiology-Cell Physiology, 301, C195, 10.1152/ajpcell.00012.2011 McIntyre, 2006, Patients receiving maintenance dialysis have more severe functionally significant skeletal muscle wasting than patients with dialysis-independent chronic kidney disease, Nephrology, Dialysis, Transplantation, 21, 2210, 10.1093/ndt/gfl064 McPherron, 1997, Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member, Nature, 387, 83, 10.1038/387083a0 McPherron, 1997, Double muscling in cattle due to mutations in the myostatin gene, Proceedings of the National Academy of Sciences of the United States of America, 94, 12457, 10.1073/pnas.94.23.12457 Menconi, 2007, Role of glucocorticoids in the molecular regulation of muscle wasting, Critical Care Medicine, 35, S602, 10.1097/01.CCM.0000279194.11328.77 Mitch, 1996, Mechanisms of muscle wasting. The role of the ubiquitin–proteasome pathway, New England Journal of Medicine, 335, 1897, 10.1056/NEJM199612193352507 Mitch, 1999, Evaluation of signals activating ubiquitin–proteasome proteolysis in a model of muscle wasting, American Journal of Physiology, 276, C1132, 10.1152/ajpcell.1999.276.5.C1132 Mitch, 1994, Metabolic acidosis stimulates muscle protein degradation by activating the ATP-dependent pathway involving ubiquitin and proteasomes, Journal of Clinical Investigation, 93, 2127, 10.1172/JCI117208 Morine, 2010, Activin IIB receptor blockade attenuates dystrophic pathology in a mouse model of Duchenne muscular dystrophy, Muscle and Nerve, 42, 722, 10.1002/mus.21743 Morley, 2001, Sarcopenia, Journal of Laboratory and Clinical Medicine, 137, 231, 10.1067/mlc.2001.113504 Morley, 2011, Sarcopenia with limited mobility: an international consensus, Journal of the American Medical Directors Association, 12, 403, 10.1016/j.jamda.2011.04.014 Morley, 2012, Sarcopenia in the elderly, Family Practice, 29, i44, 10.1093/fampra/cmr063 Morrison, 2009, A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis, Experimental Neurology, 217, 258, 10.1016/j.expneurol.2009.02.017 Mosher, 2007, A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs, PLoS Genetics, 3, e79, 10.1371/journal.pgen.0030079 Murphy, 2011, Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice, American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 301, R716, 10.1152/ajpregu.00121.2011 Murphy, 2011, Acute antibody-directed myostatin inhibition attenuates disuse muscle atrophy and weakness in mice, Journal of Applied Physiology, 110, 1065, 10.1152/japplphysiol.01183.2010 Murphy, 2010, Antibody-directed myostatin inhibition in 21-mo-old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function, FASEB Journal, 24, 4433, 10.1096/fj.10-159608 Murphy, 2010, Antibody-directed myostatin inhibition improves diaphragm pathology in young but not adult dystrophic mdx mice, American Journal of Pathology, 176, 2425, 10.2353/ajpath.2010.090932 Muttukrishna, 2000, Serum concentrations of dimeric inhibins, activin A, gonadotrophins and ovarian steroids during the menstrual cycle in older women, Human Reproduction, 15, 549, 10.1093/humrep/15.3.549 Muttukrishna, 2006, Uterine vein and maternal urinary levels of activin A and inhibin A in pre-eclampsia patients, Clinical Endocrinology, 64, 469, 10.1111/j.1365-2265.2006.02476.x Muttukrishna, 1997, Activin A and inhibin A as possible endocrine markers for pre-eclampsia, Lancet, 349, 1285, 10.1016/S0140-6736(96)09264-1 Ohsawa, 2006, Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition, Journal of Clinical Investigation, 116, 2924, 10.1172/JCI28520 Ota, 2003, Activin A induces cell proliferation of fibroblast-like synoviocytes in rheumatoid arthritis, Arthritis Rheumatism, 48, 2442, 10.1002/art.11249 Otani, 2001, Production of activin A in hyperplasia and adenocarcinoma of the human endometrium, Gynecologic Oncology, 83, 31, 10.1006/gyno.2001.6350 Parsons, 2006, Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy, American Journal of Pathology, 168, 1975, 10.2353/ajpath.2006.051316 Peters, 2004, Platelet inhibition limits TGF-beta overexpression and matrix expansion after induction of anti-thy1 glomerulonephritis, Kidney International, 65, 2238, 10.1111/j.1523-1755.2004.00630.x Piccirillo, 2012, The p97/VCP ATPase is critical in muscle atrophy and the accelerated degradation of muscle proteins, EMBO Journal, 31, 3334, 10.1038/emboj.2012.178 Pickering, 2002, Nutrition in CAPD: serum bicarbonate and the ubiquitin–proteasome system in muscle, Kidney International, 61, 1286, 10.1046/j.1523-1755.2002.00276.x Pires-Oliveira, 2010, Testosterone represses ubiquitin ligases atrogin-1 and Murf-1 expression in an androgen-sensitive rat skeletal muscle in vivo, Journal of Applied Physiology, 108, 266, 10.1152/japplphysiol.00490.2009 Pistilli, 2011, Targeting the activin type IIB receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy, American Journal of Pathology, 178, 1287, 10.1016/j.ajpath.2010.11.071 Plank, 2000, Sequential metabolic changes following induction of systemic inflammatory response in patients with severe sepsis or major blunt trauma, World Journal of Surgery, 24, 630, 10.1007/s002689910104 Plant, 2010, Cellular markers of muscle atrophy in chronic obstructive pulmonary disease, American Journal of Respiratory Cell and Molecular Biology, 42, 461, 10.1165/rcmb.2008-0382OC Polge, 2011, Muscle actin is polyubiquitinylated in vitro and in vivo and targeted for breakdown by the E3 ligase MuRF1, FASEB Journal, 25, 3790, 10.1096/fj.11-180968 Poulaki, 2004, Activin a in the regulation of corneal neovascularization and vascular endothelial growth factor expression, American Journal of Pathology, 164, 1293, 10.1016/S0002-9440(10)63216-6 Price, 1996, Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin–proteasome pathway by a mechanism including gene transcription, Journal of Clinical Investigation, 98, 1703, 10.1172/JCI118968 Rajan, 2008, Muscle wasting in chronic kidney disease: the role of the ubiquitin proteasome system and its clinical impact, Pediatric Nephrology, 23, 527, 10.1007/s00467-007-0594-z Reardon, 2001, Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy, Muscle and Nerve, 24, 893, 10.1002/mus.1086 Reid, 2001, Tumor necrosis factor-alpha and muscle wasting: a cellular perspective, Respiratory Research, 2, 269, 10.1186/rr67 Reis, 2002, Serum and tissue expression of activin a in postmenopausal women with breast cancer, Journal of Clinical Endocrinology and Metabolism, 87, 2277, 10.1210/jcem.87.5.8512 Risbridger, 2001, The contribution of inhibins and activins to malignant prostate disease, Molecular and Cellular Endocrinology, 180, 149, 10.1016/S0303-7207(01)00497-X Rose, 2009, Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy, Human Molecular Genetics, 18, 997, 10.1093/hmg/ddn426 Rosenberg, 2011, Sarcopenia: origins and clinical relevance, Clinics in Geriatric Medicine, 27, 337, 10.1016/j.cger.2011.03.003 Ruas, 2012, A PGC-1alpha isoform induced by resistance training regulates skeletal muscle hypertrophy, Cell, 151, 1319, 10.1016/j.cell.2012.10.050 Sacheck, 2007, Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases, FASEB Journal, 21, 140, 10.1096/fj.06-6604com Sacheck, 2004, IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1, American Journal of Physiology-Endocrinology and Metabolism, 4, E591, 10.1152/ajpendo.00073.2004 Sandri, 2004, Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy, Cell, 117, 399, 10.1016/S0092-8674(04)00400-3 Sandri, 2008, Signaling in muscle atrophy and hypertrophy, Physiology (Bethesda), 23, 160, 10.1152/physiol.00041.2007 Santoro, 1999, Decreased inhibin tone and increased activin A secretion characterize reproductive aging in women, Fertility and Sterility, 71, 658, 10.1016/S0015-0282(98)00529-9 Sartori, 2009, Smad2 and 3 transcription factors control muscle mass in adulthood, American Journal of Physiology-Cell Physiology, 296, C1248, 10.1152/ajpcell.00104.2009 Schakman, 2008, Mechanisms of glucocorticoid-induced myopathy, Journal of Endocrinology, 197, 1, 10.1677/JOE-07-0606 Schiaffino, 2011, Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models, Skeletal Muscle, 1, 4, 10.1186/2044-5040-1-4 Schols, 2005, Body composition and mortality in chronic obstructive pulmonary disease, American Journal of Clinical Nutrition, 82, 53, 10.1093/ajcn/82.1.53 Schuelke, 2004, Myostatin mutation associated with gross muscle hypertrophy in a child, New England Journal of Medicine, 350, 2682, 10.1056/NEJMoa040933 Seale, 2000, Pax7 is required for the specification of myogenic satellite cells, Cell, 102, 777, 10.1016/S0092-8674(00)00066-0 Sengupta, 2010, Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress, Molecular Cell, 40, 310, 10.1016/j.molcel.2010.09.026 Shan, 2013, Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1alpha-Fndc5 pathway in muscle, FASEB Journal, 10.1096/fj.12-225755 Sharma, 1999, Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct, Journal of Cellular Physiology, 180, 1, 10.1002/(SICI)1097-4652(199907)180:1<1::AID-JCP1>3.0.CO;2-V Shyu, 2006, Myostatin expression in ventricular myocardium in a rat model of volume-overload heart failure, European Journal of Clinical Investigation, 36, 713, 10.1111/j.1365-2362.2006.01718.x Sidis, 2006, Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins, Endocrinology, 147, 3586, 10.1210/en.2006-0089 Slimani, 2012, The worsening of tibialis anterior muscle atrophy during recovery post-immobilization correlates with enhanced connective tissue area, proteolysis, and apoptosis, American Journal of Physiology-Endocrinology and Metabolism, 303, E1335, 10.1152/ajpendo.00379.2012 Song, 2005, Muscle-specific expression of insulin-like growth factor-1 blocks angiotensin II-induced skeletal muscle wasting, Journal of Clinical Investigation, 115, 451, 10.1172/JCI22324 Spate, 2004, Proinflammatory cytokines and skeletal muscle, Current Opinion in Clinical Nutrition and Metabolic Care, 7, 265, 10.1097/00075197-200405000-00005 Steller, 2005, Inhibin resistance is associated with aggressive tumorigenicity of ovarian cancer cells, Molecular Cancer Research, 3, 50, 10.1158/1541-7786.50.3.1 Stitt, 2004, The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors, Molecular Cell, 14, 395, 10.1016/S1097-2765(04)00211-4 Sun, 2006, Work-induced changes in skeletal muscle IGF-1 and myostatin gene expression in uremia, Kidney International, 70, 453, 10.1038/sj.ki.5001532 Tanaka, 2004, Activin A inhibits growth-inhibitory signals by TGF-beta1 in differentiated human endometrial adenocarcinoma cells, Oncology Reports, 11, 875 Terpos, 2012, Circulating activin-A is elevated in patients with advanced multiple myeloma and correlates with extensive bone involvement and inferior survival; no alterations post-lenalidomide and dexamethasone therapy, Annals of Oncology, 23, 2681, 10.1093/annonc/mds068 Thies, 2001, GDF-8 propeptide binds to GDF-8 and antagonizes biological activity by inhibiting GDF-8 receptor binding, Growth Factors, 18, 251, 10.3109/08977190109029114 Thomas, 1997, Expression and localization of activin subunits and follistatins in tissues from men with high grade prostate cancer, Journal of Clinical Endocrinology and Metabolism, 82, 3851, 10.1210/jcem.82.11.4374 Tisdale, 2002, Cachexia in cancer patients, Nature Reviews Cancer, 2, 862, 10.1038/nrc927 Tisdale, 2009, Mechanisms of cancer cachexia, Physiological Reviews, 89, 381, 10.1152/physrev.00016.2008 Trendelenburg, 2009, Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size, American Journal of Physiology-Cell Physiology, 296, C1258, 10.1152/ajpcell.00105.2009 Tsuchida, 2009, Activin signaling as an emerging target for therapeutic interventions, Cell Communication and Signaling, 7, 15, 10.1186/1478-811X-7-15 Vallet, 2010, Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease, Proceedings of the National Academy of Sciences of the United States of America, 107, 5124, 10.1073/pnas.0911929107 Vale, 2004, Activins and inhibins and their signaling, Annals of the New York Academy of Sciences, 1038, 142, 10.1196/annals.1315.023 von Haehling, 2012, From muscle wasting to sarcopenia and myopenia: update 2012, The Journal of Cachexia, Sarcopenia and Muscle, 3, 213, 10.1007/s13539-012-0089-z Wang, 2006, Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin–proteasome pathway by defects in muscle cell signaling, Endocrinology, 147, 4160, 10.1210/en.2006-0251 Wehling, 2000, Modulation of myostatin expression during modified muscle use, FASEB Journal, 14, 103, 10.1096/fasebj.14.1.103 Wildi, 2001, Overexpression of activin A in stage IV colorectal cancer, Gut, 49, 409, 10.1136/gut.49.3.409 Wolfman, 2003, Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases, Proceedings of the National Academy of Sciences of the United States of America, 100, 15842, 10.1073/pnas.2534946100 Woodruff, 1993, Recombinant human inhibin A and recombinant human activin A regulate pituitary and ovarian function in the adult female rat, Endocrinology, 132, 2332, 10.1210/endo.132.6.8504739 Woodruff, 1990, Regulation of inhibin synthesis in the rat ovary, Annual Review of Physiology, 52, 807, 10.1146/annurev.ph.52.030190.004111 Workeneh, 2010, Review of muscle wasting associated with chronic kidney disease, American Journal of Clinical Nutrition, 91, 1128S, 10.3945/ajcn.2010.28608B Yarasheski, 2002, Serum myostatin-immunoreactive protein is increased in 60-92 year old women and men with muscle wasting, Journal of Nutrition, Health and Aging, 6, 343 Yndestad, 2009, Elevated levels of activin A in clinical and experimental pulmonary hypertension, Journal of Applied Physiology, 106, 1356, 10.1152/japplphysiol.90719.2008 Yndestad, 2004, Elevated levels of activin A in heart failure: potential role in myocardial remodeling, Circulation, 109, 1379, 10.1161/01.CIR.0000120704.97934.41 Yoshinaga, 2003, Clinical significance of the expression of activin A in esophageal carcinoma, International Journal of Oncology, 22, 75 Yoshinaga, 2008, Activin a causes cancer cell aggressiveness in esophageal squamous cell carcinoma cells, Annals of Surgical Oncology, 15, 96, 10.1245/s10434-007-9631-1 Yu, 1997, Production of activin A and its roles in inflammation and hematopoiesis, Cytokines, Cellular and Molecular Therapy, 3, 169 Zachwieja, 1999, Plasma myostatin-immunoreactive protein is increased after prolonged bed rest with low-dose T3 administration, Journal of Gravitational Physiology, 6, 11 Zhang, 2011, Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway, Diabetologia, 54, 1491, 10.1007/s00125-011-2079-7 Zhang, 2012, Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice, Diabetologia, 55, 183, 10.1007/s00125-011-2304-4 Zhang, 2009, IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting, Journal of the American Society of Nephrology, 20, 604, 10.1681/ASN.2008060628 Zhang, 2010, Satellite cell dysfunction and impaired IGF-1 signaling contribute to muscle atrophy in chronic kidney disease, Journal of the American Society of Nephrology, 21, 419, 10.1681/ASN.2009060571 Zhang, 2011, Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease, FASEB Journal, 25, 1653, 10.1096/fj.10-176917 Zhang, 1997, Regulation of growth and prostatic marker expression by activin A in an androgen-sensitive prostate cancer cell line LNCAP, Biochemical and Biophysical Research Communications, 234, 362, 10.1006/bbrc.1997.6649 Zhao, 2007, FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells, Cell Metabolism, 6, 472, 10.1016/j.cmet.2007.11.004 Zheng, 2010, FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy, FASEB Journal, 24, 2660, 10.1096/fj.09-151480 Zhou, 2010, Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival, Cell, 142, 531, 10.1016/j.cell.2010.07.011 Zimmers, 2002, Induction of cachexia in mice by systemically administered myostatin, Science, 296, 1486, 10.1126/science.1069525 Zugmaier, 1991, Transforming growth factor beta 1 induces cachexia and systemic fibrosis without an antitumor effect in nude mice, Cancer Research, 51, 3590