{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T19:51:48Z","timestamp":1782330708923,"version":"3.54.5"},"reference-count":106,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,6,28]],"date-time":"2020-06-28T00:00:00Z","timestamp":1593302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2018-04205"],"award-info":[{"award-number":["RGPIN-2018-04205"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Cancer cachexia is a debilitating condition characterized by an extreme loss of skeletal muscle mass, which negatively impacts patients\u2019 quality of life, reduces their ability to sustain anti-cancer therapies, and increases the risk of mortality. Recent discoveries have identified the myostatin\/activin A\/ActRIIB pathway as critical to muscle wasting by inducing satellite cell quiescence and increasing muscle-specific ubiquitin ligases responsible for atrophy. Remarkably, pharmacological blockade of the ActRIIB pathway has been shown to reverse muscle wasting and prolong the survival time of tumor-bearing animals. To explore the implications of this signaling pathway and potential therapeutic targets in cachexia, we construct a novel mathematical model of muscle tissue subjected to tumor-derived cachectic factors. The model formulation tracks the intercellular interactions between cancer cell, satellite cell, and muscle cell populations. The model is parameterized by fitting to colon-26 mouse model data, and the analysis provides insight into tissue growth in healthy, cancerous, and post-cachexia treatment conditions. Model predictions suggest that cachexia fundamentally alters muscle tissue health, as measured by the stem cell ratio, and this is only partially recovered by anti-cachexia treatment. Our mathematical findings suggest that after blocking the myostatin\/activin A pathway, partial recovery of cancer-induced muscle loss requires the activation and proliferation of the satellite cell compartment with a functional differentiation program.<\/jats:p>","DOI":"10.3390\/jcm9072029","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T14:27:29Z","timestamp":1593527249000},"page":"2029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mathematical Model of Muscle Wasting in Cancer Cachexia"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7654-8804","authenticated-orcid":false,"given":"Suzan","family":"Farhang-Sardroodi","sequence":"first","affiliation":[{"name":"Department of Mathematics, Ryerson University, 350 Victoria St, Toronto, ON M5B 2K3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3226-724X","authenticated-orcid":false,"given":"Kathleen P.","family":"Wilkie","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Ryerson University, 350 Victoria St, Toronto, ON M5B 2K3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/nrc927","article-title":"Cachexia in cancer patients","volume":"2","author":"Tisdale","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/ncpendmet0247","article-title":"The need for a standardized definition for cachexia in chronic illness","volume":"2","author":"Springer","year":"2006","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.clnu.2008.06.013","article-title":"Cachexia: A new definition","volume":"27","author":"Evans","year":"2008","journal-title":"Clin. Nutr. Espen"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2011\/601434","article-title":"Cancer cachexia: Mechanisms and clinical implications","volume":"2011","author":"Donohoe","year":"2011","journal-title":"Gastroent. Res. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13539-010-0002-6","article-title":"Cachexia as a major underestimated and unmet medical need: Facts and numbers","volume":"1","author":"Anker","year":"2010","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_6","first-page":"491","article-title":"Prognostic effect of weight loss prior to chemotherapy in cancer patients","volume":"69","author":"Dewys","year":"1980","journal-title":"Am. J. Med. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1093\/ajcn\/83.6.1345","article-title":"Definition of cancer cachexia: Effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis","volume":"83","author":"Fearon","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1152\/physrev.00016.2008","article-title":"Mechanisms of cancer cachexia","volume":"89","author":"Tisdale","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1177\/0148607188012003286","article-title":"Cancer cachexia","volume":"12","author":"Kern","year":"1988","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1242\/dmm.007658","article-title":"InACTIVatINg cancer cachexia","volume":"4","author":"Mathew","year":"2011","journal-title":"Dis. Model. Mech."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1097\/MPA.0000000000001124","article-title":"Pancreatic Cancer-Induced Cachexia and Relevant Mouse Models","volume":"47","author":"Henderson","year":"2018","journal-title":"Pancreas"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1146\/annurev.nu.02.070182.001425","article-title":"Metabolic approaches to cancer cachexia","volume":"2","author":"Lawson","year":"1982","journal-title":"Annu. Rev. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1470-2045(10)70218-7","article-title":"Definition and classification of cancer cachexia: An international consensus","volume":"12","author":"Fearon","year":"2011","journal-title":"Lancet. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.4251\/wjgo.v7.i4.17","article-title":"Cancer cachexia, mechanism and treatment","volume":"7","author":"Aoyagi","year":"2015","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1200\/JOP.2016.016832","article-title":"Cancer cachexia: Beyond weight loss","volume":"12","author":"Bruggeman","year":"2016","journal-title":"J. Oncol. Pract."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Del Fabbro, E., Inui, A., and Strasser, F. (2012). Overview of cancer cachexia. Cancer Cachexia, Springer.","DOI":"10.1007\/978-1-910315-07-1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"129","DOI":"10.4103\/0973-1075.73644","article-title":"Treatment of cachexia in oncology","volume":"16","author":"Tazi","year":"2010","journal-title":"Indian J. Palliat. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.2147\/TCRM.S196802","article-title":"Emerging Treatment Options For Cancer-Associated Cachexia: A Literature Review","volume":"15","author":"Naito","year":"2019","journal-title":"Ther. Clin. Risk. Manag."},{"key":"ref_19","first-page":"629","article-title":"Systemic Inflammation in Cachexia\u2014Is Tumor Cytokine Expression Profile the Culprit?","volume":"6","author":"Lima","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_20","first-page":"1091","article-title":"Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: Relationship to acute phase response and survival","volume":"21","author":"Moses","year":"2009","journal-title":"Oncol. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1097\/JES.0b013e3181f44f11","article-title":"Interleukin-6 as a key regulator of muscle mass during cachexia","volume":"38","author":"Carson","year":"2010","journal-title":"Exerc. Sport Sci. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"791060","DOI":"10.1155\/2015\/791060","article-title":"Cancer as a proinflammatory environment: Metastasis and cachexia","volume":"2015","author":"Carnier","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.lfs.2016.11.033","article-title":"TNF-\u03b1 and cancer cachexia: Molecular insights and clinical implications","volume":"170","author":"Patel","year":"2017","journal-title":"Life Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.canlet.2020.04.017","article-title":"Macrophages potentiate STAT3 signaling in skeletal muscles and regulate pancreatic cancer cachexia","volume":"484","author":"Shukla","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4821","DOI":"10.1172\/JCI68523","article-title":"NF-\u03baB\u2013mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia","volume":"123","author":"He","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e54095","DOI":"10.7554\/eLife.54095","article-title":"Circulating myeloid cells invade the central nervous system to mediate cachexia during pancreatic cancer","volume":"9","author":"Burfeind","year":"2020","journal-title":"eLife"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1016\/j.biocel.2013.05.019","article-title":"Myostatin\/activin pathway antagonism: Molecular basis and therapeutic potential","volume":"45","author":"Han","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1477-2574.2010.00178.x","article-title":"Cachexia in Pancreatic Cancer: New Treatment Options and Measures of Success","volume":"12","author":"Fearon","year":"2010","journal-title":"HPB"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0092-8674(04)00400-3","article-title":"Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy","volume":"117","author":"Sandri","year":"2004","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1016\/j.biocel.2005.04.018","article-title":"Skeletal muscle hypertrophy and atrophy signaling pathways","volume":"37","author":"Glass","year":"2005","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.cell.2010.07.011","article-title":"Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival","volume":"142","author":"Zhou","year":"2010","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s13539-011-0035-5","article-title":"The role of myostatin in muscle wasting: An overview","volume":"2","author":"Elkina","year":"2011","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1097\/SPC.0b013e32834bddf9","article-title":"Targeting the myostatin signaling pathway to treat muscle wasting diseases","volume":"5","author":"Han","year":"2011","journal-title":"Curr. Opin. Support. Pa."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1083\/jcb.200207056","article-title":"Myostatin negatively regulates satellite cell activation and self-renewal","volume":"162","author":"McCroskery","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1016\/j.bbrc.2009.12.123","article-title":"Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia","volume":"391","author":"Klimek","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.1096\/fj.10-159608","article-title":"Antibody-directed myostatin inhibition in 21-mo-old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function","volume":"24","author":"Murphy","year":"2010","journal-title":"FASEB J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s13539-011-0049-z","article-title":"Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance","volume":"3","author":"Busquets","year":"2012","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/0092-8674(91)90549-E","article-title":"Expression cloning of an activin receptor, a predicted transmembrane serine kinase","volume":"65","author":"Mathews","year":"1991","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0092-8674(92)90209-U","article-title":"Novel activin receptors: Distinct genes and alternative mRNA splicing generate a repertoire of serine\/threonine kinase receptors","volume":"68","author":"Attisano","year":"1992","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1101\/gad.11.14.1812","article-title":"The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse","volume":"11","author":"Oh","year":"1997","journal-title":"Genes Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9306","DOI":"10.1073\/pnas.151270098","article-title":"Regulation of myostatin activity and muscle growth","volume":"98","author":"Lee","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.cmet.2007.11.001","article-title":"FoxO3 controls autophagy in skeletal muscle in vivo","volume":"6","author":"Mammucari","year":"2007","journal-title":"Cell Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cmet.2007.11.004","article-title":"FoxO3 coordinately activates protein degradation by the autophagic\/lysosomal and proteasomal pathways in atrophying muscle cells","volume":"6","author":"Zhao","year":"2007","journal-title":"Cell Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1083\/jcb.200901052","article-title":"During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation","volume":"185","author":"Cohen","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.cell.2010.08.004","article-title":"Reversing cachexia","volume":"142","author":"Tisdale","year":"2010","journal-title":"Cell"},{"key":"ref_46","first-page":"289","article-title":"Mathematical models of tumor-host interactions","volume":"11","author":"Gatenby","year":"1998","journal-title":"Cancer J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/421321a","article-title":"Mathematical oncology: Cancer summed up","volume":"421","author":"Gatenby","year":"2003","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/j.bulm.2003.11.002","article-title":"A history of the study of solid tumour growth: The contribution of mathematical modelling","volume":"66","author":"Araujo","year":"2004","journal-title":"Bull. Math. Biol."},{"key":"ref_49","unstructured":"Wheldon, T. (1988). Mathematical Models in Cancer Research, CRC Press."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5921","DOI":"10.1158\/0008-5472.CAN-16-1293","article-title":"Concepts in cancer modeling: A brief history","volume":"76","author":"Thomas","year":"2016","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.addr.2018.07.013","article-title":"Computational modelling of drug delivery to solid tumour: Understanding the interplay between chemotherapeutics and biological system for optimised delivery systems","volume":"132","author":"Zhan","year":"2018","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"041005","DOI":"10.1088\/1478-3975\/ab1a09","article-title":"The 2019 mathematical oncology roadmap","volume":"16","author":"Rockne","year":"2019","journal-title":"Phys. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Hadjicharalambous, M., Wijeratne, P.A., and Vavourakis, V. (2020). From tumour perfusion to drug delivery and clinical translation of in silico cancer models. Methods.","DOI":"10.1016\/j.ymeth.2020.02.010"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nrc4029","article-title":"The mathematics of cancer: Integrating quantitative models","volume":"15","author":"Altrock","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Houston, M.T., Cameron, A.N., and Gutierrez, J.B. (2018). A review of mathematical models for muscular dystrophy: A systems biology approach. PLoS Curr. Muscular Dystrophy, 1.","DOI":"10.1371\/currents.md.6af74d0cec0834554dac78f0045cfded"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8589","DOI":"10.1002\/mma.4908","article-title":"A mathematical model of skeletal muscle regeneration","volume":"41","author":"Stephenson","year":"2018","journal-title":"Math. Method Appl. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1097\/MCO.0b013e3282f9ae4d","article-title":"Computational Modeling of Cancer Cachexia","volume":"11","author":"Hall","year":"2009","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12976-015-0015-0","article-title":"Modeling the energetic cost of cancer as a result of altered energy metabolism: Implications for cachexia","volume":"12","author":"Friesen","year":"2015","journal-title":"Theor. Biol. Med. Model."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wilkie, K.P., and Aktar, F. (2020). Mathematically modelling inflammation as a promoter of tumour growth. Math. Med. Biol.","DOI":"10.1101\/2020.03.08.982918"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"18983","DOI":"10.1073\/pnas.1107621108","article-title":"Evolutionary dynamics of feedback escape and the development of stem-cell\u2013driven cancers","volume":"108","author":"Komarova","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1152\/jappl.2000.89.1.81","article-title":"Skeletal muscle mass and distribution in 468 men and women aged 18\u201388 yr","volume":"89","author":"Janssen","year":"2000","journal-title":"J. Appl. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1083\/jcb.9.2.493","article-title":"Satellite cell of skeletal muscle fibers","volume":"9","author":"Mauro","year":"1961","journal-title":"J. Biophys. Biochem. Cytol."},{"key":"ref_63","first-page":"233","article-title":"Population of muscle satellite cells in relation to age and mitotic activity","volume":"3","author":"Allbrook","year":"1971","journal-title":"J. Pathol"},{"key":"ref_64","first-page":"503","article-title":"Muscle satellite cell numbers during the postnatal period","volume":"110","author":"Hellmuth","year":"1971","journal-title":"J. Anat."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/ar.1091800405","article-title":"A quantitative study of the satellite cell population in postnatal mouse lumbrical muscle","volume":"180","author":"Schultz","year":"1974","journal-title":"Anat. Rec."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1101\/sqb.2008.73.064","article-title":"The molecular regulation of muscle stem cell function","volume":"73","author":"Rudnicki","year":"2008","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/ar.1091880206","article-title":"Myogenic cell formation in regenerating rat skeletal muscle injured by mincing II. An autoradiographic study","volume":"188","author":"Snow","year":"1977","journal-title":"Anat. Rec."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/0012-1606(86)90235-6","article-title":"A satellite cell mitogen from crushed adult muscle","volume":"115","author":"Bischoff","year":"1986","journal-title":"Dev. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/ar.1091900212","article-title":"Changes in the satellite cells of growing muscle following denervation","volume":"190","author":"Schultz","year":"1978","journal-title":"Anat. Rec."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.tcb.2005.10.007","article-title":"Stem cells in postnatal myogenesis: Molecular mechanisms of satellite cell quiescence, activation and replenishment","volume":"15","author":"Dhawan","year":"2005","journal-title":"Trends Cell Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"S12","DOI":"10.1016\/j.numecd.2012.02.002","article-title":"Role of satellite cells in muscle growth and maintenance of muscle mass","volume":"23","author":"Pallafacchina","year":"2013","journal-title":"Nutr. Metab. Carbiovasc. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1152\/physrev.00043.2011","article-title":"Satellite cells and the muscle stem cell niche","volume":"93","author":"Yin","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Lander, A.D., Gokoffski, K.K., Wan, F.Y., Nie, Q., and Calof, A.L. (2009). Cell lineages and the logic of proliferative control. PLoS Biol., 7.","DOI":"10.1371\/journal.pbio.1000015"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.stem.2007.12.012","article-title":"Niche regulation of muscle satellite cell self-renewal and differentiation","volume":"2","author":"Kuang","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_75","unstructured":"(2018, September 20). Charles River CD2F1 (CDF1) Mouse Growth Chart. Available online: https:\/\/www.criver.com\/products-services\/find-model\/cd2f1-cdf1-mouse."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1145\/29380.29864","article-title":"Minimizing multimodal functions of continuous variables with the \u201csimulated annealing\u201d algorithm Corrigenda for this article is available here","volume":"13","author":"Corana","year":"1987","journal-title":"ACM Trans. Math. Softw."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1214\/ss\/1177011077","article-title":"Simulated annealing","volume":"8","author":"Bertsimas","year":"1993","journal-title":"Stat. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1097\/MAJ.0000000000000511","article-title":"Mechanisms of cachexia in chronic disease states","volume":"350","author":"Yoshida","year":"2015","journal-title":"Am. J. Med. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Penna, F., Costamagna, D., Fanzani, A., Bonelli, G., Baccino, F.M., and Costelli, P. (2010). Muscle wasting and impaired myogenesis in tumor bearing mice are prevented by ERK inhibition. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013604"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-14290-3","article-title":"Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington\u2019s disease mice","volume":"7","author":"Bondulich","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1097\/00006534-200207000-00027","article-title":"Skeletal muscle denervation increases satellite cell susceptibility to apoptosis","volume":"110","author":"Jejurikar","year":"2002","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1023\/A:1026127307457","article-title":"Satellite cell depletion in degenerative skeletal muscle","volume":"8","author":"Jejurikar","year":"2003","journal-title":"Apoptosis"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1007\/s00421-006-0197-6","article-title":"Skeletal muscle atrophy increases cell proliferation in mice gastrocnemius during the first week of hindlimb suspension","volume":"97","author":"Ferreira","year":"2006","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Guo, B.S., Cheung, K.K., Yeung, S.S., Zhang, B.T., and Yeung, E.W. (2012). Electrical stimulation influences satellite cell proliferation and apoptosis in unloading-induced muscle atrophy in mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030348"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.semcdb.2015.09.009","article-title":"Impaired regeneration: A role for the muscle microenvironment in cancer cachexia","volume":"Volume 54","author":"Talbert","year":"2016","journal-title":"Seminars in Cell & Developmental Biology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1158\/0008-5472.CAN-03-2524","article-title":"Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administration of anticancer agents","volume":"64","author":"Simeoni","year":"2004","journal-title":"Cancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S1097-2765(04)00211-4","article-title":"The IGF-1\/PI3K\/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors","volume":"14","author":"Stitt","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/nrm2297","article-title":"TGF\u03b2\u2013SMAD signal transduction: Molecular specificity and functional flexibility","volume":"8","author":"Schmierer","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_89","first-page":"3957","article-title":"Inhibition of myostatin reverses muscle fibrosis through apoptosis","volume":"125","author":"Li","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/mus.21944","article-title":"Soluble activin receptor type IIB increases forward pulling tension in the mdx mouse","volume":"43","author":"Bruemmer","year":"2011","journal-title":"Muscle Nerve"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1002\/mus.21743","article-title":"Activin IIB receptor blockade attenuates dystrophic pathology in a mouse model of Duchenne muscular dystrophy","volume":"42","author":"Morine","year":"2010","journal-title":"Muscle Nerve"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.ajpath.2010.11.071","article-title":"Targeting the activin type IIB receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy","volume":"178","author":"Pistilli","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/ijo.2009.162","article-title":"The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity","volume":"33","author":"Akpan","year":"2009","journal-title":"Int. J. Obes."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s00125-011-2304-4","article-title":"Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice","volume":"55","author":"Zhang","year":"2012","journal-title":"Diabetologia"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4289","DOI":"10.1210\/en.2010-0134","article-title":"A soluble activin receptor type IIb prevents the effects of androgen deprivation on body composition and bone health","volume":"151","author":"Koncarevic","year":"2010","journal-title":"Endocrinology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.ajpath.2010.10.035","article-title":"Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice","volume":"178","author":"Lawlor","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.expneurol.2009.02.017","article-title":"A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis","volume":"217","author":"Morrison","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1172\/JCI28520","article-title":"Muscular atrophy of caveolin-3\u2013deficient mice is rescued by myostatin inhibition","volume":"116","author":"Ohsawa","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"12448","DOI":"10.1073\/pnas.1707925114","article-title":"Blockade of activin type II receptors with a dual anti-ActRIIA\/IIB antibody is critical to promote maximal skeletal muscle hypertrophy","volume":"114","author":"Morvan","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"C1248","DOI":"10.1152\/ajpcell.00104.2009","article-title":"Smad2 and 3 transcription factors control muscle mass in adulthood","volume":"296","author":"Sartori","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"7479","DOI":"10.1073\/pnas.0811129106","article-title":"Muscle hypertrophy driven by myostatin blockade does not require stem\/precursor-cell activity","volume":"106","author":"Amthor","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1113\/jphysiol.2011.226001","article-title":"Myostatin inhibition induces muscle fibre hypertrophy prior to satellite cell activation","volume":"590","author":"Wang","year":"2012","journal-title":"J. Physiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"E2353","DOI":"10.1073\/pnas.1206410109","article-title":"Role of satellite cells versus myofibers in muscle hypertrophy induced by inhibition of the myostatin\/activin signaling pathway","volume":"109","author":"Lee","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_104","first-page":"181","article-title":"Cancer cachexia and immunomodulation","volume":"10","author":"Myrianthefs","year":"2005","journal-title":"J. BUON."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e200","DOI":"10.1038\/oncsis.2016.3","article-title":"Understanding cachexia as a cancer metabolism syndrome","volume":"5","author":"Porporato","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Fonseca, G.W.P.d., Farkas, J., Dora, E., von Haehling, S., and Lainscak, M. (2020). Cancer Cachexia and Related Metabolic Dysfunction. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072321"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/7\/2029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:44:08Z","timestamp":1760175848000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/7\/2029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,28]]},"references-count":106,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["jcm9072029"],"URL":"https:\/\/doi.org\/10.3390\/jcm9072029","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.03.30.016709","asserted-by":"object"}]},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,28]]}}}