{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:01:29Z","timestamp":1791302489373,"version":"4.1.0"},"reference-count":50,"publisher":"The Endocrine Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,12,1]]},"abstract":"<jats:p>Androgens increase skeletal muscle mass, but their clinical use is hampered by a lack of tissue selectivity and subsequent side effects. Selective androgen receptor modulators elicit muscle-anabolic effects while only sparingly affecting reproductive tissues. The selective androgen receptor modulator, GTx-024 (enobosarm), is being investigated for cancer cachexia, sarcopenia, and muscle wasting diseases. Here we investigate the role of muscle androgen receptor (AR) in the anabolic effect of GTx-024. In mice lacking AR in the satellite cell lineage (satARKO), the weight of the androgen-sensitive levator ani muscle was lower but was decreased further upon orchidectomy. GTx-024 was as effective as DHT in restoring levator ani weights to sham levels. Expression of the muscle-specific, androgen-responsive genes S-adenosylmethionine decarboxylase and myostatin was decreased by orchidectomy and restored by GTx-024 and DHT in control mice, whereas the expression was low and unaffected by androgen status in satARKO. In contrast, insulin-like growth factor 1Ea expression was not different between satARKO and control muscle, decreased upon castration, and was restored by DHT and GTx-024 in both genotypes. These data indicate that GTx-024 does not selectively modulate AR in the satellite cell lineage and that cells outside this lineage remain androgen responsive in satARKO muscle. Indeed, residual AR-positive cells were present in satARKO muscle, coexpressing the fibroblast-lineage marker vimentin. AR positive, muscle-resident fibroblasts could therefore be involved in the indirect effects of androgens on muscle. In conclusion, both DHT and GTx-024 target AR pathways in the satellite cell lineage, but cells outside this lineage also contribute to the anabolic effects of androgens.<\/jats:p>","DOI":"10.1210\/en.2015-1479","type":"journal-article","created":{"date-parts":[[2015,9,22]],"date-time":"2015-09-22T17:00:39Z","timestamp":1442941239000},"page":"4522-4533","source":"Crossref","is-referenced-by-count":50,"title":["Enobosarm (GTx-024) Modulates Adult Skeletal Muscle Mass Independently of the Androgen Receptor in the Satellite Cell Lineage"],"prefix":"10.1210","volume":"156","author":[{"given":"Vanessa","family":"Dubois","sequence":"first","affiliation":[{"name":"Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Simitsidellis","sequence":"first","affiliation":[{"name":"Medical Research Council Centre for Inflammation Research (I.S., P.T.K.S.), University of Edinburgh, Edinburgh EH16 4SB, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u00ebl R.","family":"Laurent","sequence":"first","affiliation":[{"name":"Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium"},{"name":"Department of Cellular and Molecular Medicine, Department of Gerontology and Geriatrics (M.R.L.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferran","family":"Jardi","sequence":"first","affiliation":[{"name":"Clinical and Experimental Endocrinology (F.J., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippa T. K.","family":"Saunders","sequence":"first","affiliation":[{"name":"Medical Research Council Centre for Inflammation Research (I.S., P.T.K.S.), University of Edinburgh, Edinburgh EH16 4SB, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Vanderschueren","sequence":"first","affiliation":[{"name":"Clinical and Experimental Endocrinology (F.J., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Claessens","sequence":"first","affiliation":[{"name":"Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2015,9,22]]},"reference":[{"key":"2020071612421673700_B1","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1007\/s00018-011-0883-3","article-title":"Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions","volume":"69","author":"Dubois","year":"2012","journal-title":"Cell Mol Life Sci"},{"key":"2020071612421673700_B2","doi-asserted-by":"crossref","first-page":"3374","DOI":"10.1210\/en.2009-1339","article-title":"Deletion of androgen receptor in the smooth muscle of the seminal vesicles impairs secretory function and alters its responsiveness to exogenous testosterone and estradiol","volume":"151","author":"Welsh","year":"2010","journal-title":"Endocrinology"},{"issue":"6","key":"2020071612421673700_B3","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1210\/er.2014-1024","article-title":"Sex steroid actions in male bone","volume":"35","author":"Vanderschueren","year":"2014","journal-title":"Endocr Rev"},{"key":"2020071612421673700_B4","doi-asserted-by":"crossref","first-page":"e008","DOI":"10.1621\/nrs.06008","article-title":"Diverse roles of androgen receptor (AR) domains in AR-mediated signaling","volume":"6","author":"Claessens","year":"2008","journal-title":"Nucl Recept Signal"},{"key":"2020071612421673700_B5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1056\/NEJM199607043350101","article-title":"The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men","volume":"335","author":"Bhasin","year":"1996","journal-title":"N Engl J Med"},{"key":"2020071612421673700_B6","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1056\/NEJMoa1206168","article-title":"Gonadal steroids and body composition, strength, and sexual function in men","volume":"369","author":"Finkelstein","year":"2013","journal-title":"N Engl J Med"},{"key":"2020071612421673700_B7","doi-asserted-by":"crossref","first-page":"3597","DOI":"10.1021\/jm900280m","article-title":"Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit","volume":"52","author":"Mohler","year":"2009","journal-title":"J Med Chem"},{"key":"2020071612421673700_B8","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1124\/jpet.105.088344","article-title":"The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators","volume":"315","author":"Kim","year":"2005","journal-title":"J Pharmacol Exp Ther"},{"key":"2020071612421673700_B9","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s13539-011-0034-6","article-title":"The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial","volume":"2","author":"Dalton","year":"2011","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"2020071612421673700_B10","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S1470-2045(13)70055-X","article-title":"Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial","volume":"14","author":"Dobs","year":"2013","journal-title":"Lancet Oncol"},{"key":"2020071612421673700_B11","doi-asserted-by":"crossref","first-page":"3558","DOI":"10.1210\/en.2008-1509","article-title":"Androgen signaling in myocytes contributes to the maintenance of muscle mass and fiber type regulation but not to muscle strength or fatigue","volume":"150","author":"Ophoff","year":"2009","journal-title":"Endocrinology"},{"key":"2020071612421673700_B12","doi-asserted-by":"crossref","first-page":"14327","DOI":"10.1073\/pnas.1009536107","article-title":"Myocytic androgen receptor controls the strength but not the mass of limb muscles","volume":"107","author":"Chambon","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612421673700_B13","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1111\/j.1365-2826.2007.01592.x","article-title":"Androgen receptor expression in the levator ani muscle of male mice","volume":"19","author":"Johansen","year":"2007","journal-title":"J Neuroendocrinol"},{"key":"2020071612421673700_B14","doi-asserted-by":"crossref","first-page":"5245","DOI":"10.1210\/jc.2004-0084","article-title":"Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment","volume":"89","author":"Sinha-Hikim","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612421673700_B15","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1096\/fj.14-249748","article-title":"A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle","volume":"28","author":"Dubois","year":"2014","journal-title":"FASEB J"},{"key":"2020071612421673700_B16","doi-asserted-by":"crossref","first-page":"477","DOI":"10.2337\/diab.39.4.477","article-title":"Bone and mineral metabolism in BB rats with long-term diabetes. Decreased bone turnover and osteoporosis","volume":"39","author":"Verhaeghe","year":"1990","journal-title":"Diabetes"},{"key":"2020071612421673700_B17","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1128\/MCB.00151-12","article-title":"Evidence for DNA-binding domain-ligand-binding domain communications in the androgen receptor","volume":"32","author":"Helsen","year":"2012","journal-title":"Mol Cell Biol"},{"key":"2020071612421673700_B18","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1210\/me.2009-0310","article-title":"The rules of DNA recognition by the androgen receptor","volume":"24","author":"Denayer","year":"2010","journal-title":"Mol Endocrinol"},{"key":"2020071612421673700_B19","doi-asserted-by":"crossref","first-page":"35191","DOI":"10.1074\/jbc.M205928200","article-title":"Functional interplay between two response elements with distinct binding characteristics dictates androgen specificity of the mouse sex-limited protein enhancer","volume":"277","author":"Verrijdt","year":"2002","journal-title":"J Biol Chem"},{"key":"2020071612421673700_B20","doi-asserted-by":"crossref","first-page":"e86378","DOI":"10.1371\/journal.pone.0086378","article-title":"Evidence from a mouse model that epithelial cell migration and mesenchymal-epithelial transition contribute to rapid restoration of uterine tissue integrity during menstruation","volume":"9","author":"Cousins","year":"2014","journal-title":"PLoS One"},{"key":"2020071612421673700_B21","doi-asserted-by":"crossref","first-page":"3437","DOI":"10.1210\/en.2009-0438","article-title":"Unraveling androgen action in muscle: genetic tools probing cellular mechanisms","volume":"150","author":"MacLean","year":"2009","journal-title":"Endocrinology"},{"key":"2020071612421673700_B22","doi-asserted-by":"crossref","first-page":"2676","DOI":"10.1096\/fj.08-105726","article-title":"Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice","volume":"22","author":"MacLean","year":"2008","journal-title":"FASEB J"},{"key":"2020071612421673700_B23","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1210\/me.2010-0138","article-title":"Research resource: the androgen receptor modulates expression of genes with critical roles in muscle development and function","volume":"24","author":"Wyce","year":"2010","journal-title":"Mol Endocrinol"},{"key":"2020071612421673700_B24","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ghir.2004.11.001","article-title":"Reconciling data from transgenic mice that overexpress IGF-I specifically in skeletal muscle","volume":"15","author":"Shavlakadze","year":"2005","journal-title":"Growth Horm IGF Res"},{"key":"2020071612421673700_B25","doi-asserted-by":"crossref","first-page":"E483","DOI":"10.1152\/ajpendo.00191.2001","article-title":"Role of IGF-I and IGF-binding proteins within diaphragm muscle in modulating the effects of nandrolone","volume":"282","author":"Lewis","year":"2002","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612421673700_B26","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/jcp.20000","article-title":"IGF-I mRNA levels in bovine satellite cell cultures: effects of fusion and anabolic steroid treatment","volume":"201","author":"Kamanga-Sollo","year":"2004","journal-title":"J Cell Physiol"},{"key":"2020071612421673700_B27","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s00223-012-9622-5","article-title":"Musculoskeletal frailty: a geriatric syndrome at the core of fracture occurrence in older age","volume":"91","author":"Gielen","year":"2012","journal-title":"Calcif Tissue Int"},{"key":"2020071612421673700_B28","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.maturitas.2013.03.014","article-title":"Mechanism and novel therapeutic approaches to wasting in chronic disease","volume":"75","author":"Ebner","year":"2013","journal-title":"Maturitas"},{"key":"2020071612421673700_B29","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1097\/SPC.0000000000000015","article-title":"Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer","volume":"7","author":"Dalton","year":"2013","journal-title":"Curr Opin Support Palliat Care"},{"key":"2020071612421673700_B30","doi-asserted-by":"crossref","first-page":"RC46","DOI":"10.1523\/JNEUROSCI.19-24-j0004.1999","article-title":"Regulation of terminal Schwann cell number at the adult neuromuscular junction","volume":"19","author":"Lubischer","year":"1999","journal-title":"J Neurosci"},{"key":"2020071612421673700_B31","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1002\/cne.20088","article-title":"Androgen receptor immunoreactivity in skeletal muscle: enrichment at the neuromuscular junction","volume":"473","author":"Monks","year":"2004","journal-title":"J Comp Neurol"},{"key":"2020071612421673700_B32","doi-asserted-by":"crossref","first-page":"4887","DOI":"10.1210\/en.2005-0572","article-title":"Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats","volume":"146","author":"Gao","year":"2005","journal-title":"Endocrinology"},{"key":"2020071612421673700_B33","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1002\/jcp.22569","article-title":"Polyamines, androgens, and skeletal muscle hypertrophy","volume":"226","author":"Lee","year":"2011","journal-title":"J Cell Physiol"},{"key":"2020071612421673700_B34","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/387083a0","article-title":"Regulation of skeletal muscle mass in mice by a new TGF-\u03b2 superfamily member","volume":"387","author":"McPherron","year":"1997","journal-title":"Nature"},{"key":"2020071612421673700_B35","doi-asserted-by":"crossref","first-page":"E327","DOI":"10.1152\/ajpendo.00402.2010","article-title":"Voluntary running, skeletal muscle gene expression, and signaling inversely regulated by orchidectomy and testosterone replacement","volume":"300","author":"Ibebunjo","year":"2011","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612421673700_B36","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.bbrc.2008.11.016","article-title":"Physical activity in the androgen receptor knockout mouse: evidence for reversal of androgen deficiency on cancellous bone","volume":"378","author":"Ophoff","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071612421673700_B37","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1210\/en.2008-1478","article-title":"Sexual differentiation of the spinal nucleus of the bulbocavernosus is not mediated solely by androgen receptors in muscle fibers","volume":"150","author":"Niel","year":"2009","journal-title":"Endocrinology"},{"key":"2020071612421673700_B38","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1242\/dev.057463","article-title":"Connective tissue fibroblasts and Tcf4 regulate myogenesis","volume":"138","author":"Mathew","year":"2011","journal-title":"Development"},{"key":"2020071612421673700_B39","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.1242\/dev.064162","article-title":"Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration","volume":"138","author":"Murphy","year":"2011","journal-title":"Development"},{"key":"2020071612421673700_B40","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/0012-1606(90)90048-N","article-title":"Paracrine control of myoblast proliferation and differentiation by fibroblasts","volume":"140","author":"Quinn","year":"1990","journal-title":"Dev Biol"},{"key":"2020071612421673700_B41","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s10544-012-9709-9","article-title":"Fibroblasts influence muscle progenitor differentiation and alignment in contact independent and dependent manners in organized co-culture devices","volume":"15","author":"Rao","year":"2013","journal-title":"Biomed Microdevices"},{"key":"2020071612421673700_B42","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1007\/s12032-013-0674-9","article-title":"Androgen receptor in human prostate cancer-associated fibroblasts promotes prostate cancer epithelial cell growth and invasion","volume":"30","author":"Yu","year":"2013","journal-title":"Med Oncol"},{"key":"2020071612421673700_B43","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1210\/en.2014-1008","article-title":"Nonmyocytic androgen receptor regulates the sexually dimorphic development of the embryonic bulbocavernosus muscle","volume":"155","author":"Ipulan","year":"2014","journal-title":"Endocrinology"},{"key":"2020071612421673700_B44","doi-asserted-by":"crossref","first-page":"5081","DOI":"10.1210\/en.2003-0741","article-title":"Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1\/2 pluripotent cells through an androgen receptor-mediated pathway","volume":"144","author":"Singh","year":"2003","journal-title":"Endocrinology"},{"key":"2020071612421673700_B45","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1210\/en.2010-0802","article-title":"The role of GH and IGF-I in mediating anabolic effects of testosterone on androgen-responsive muscle","volume":"152","author":"Serra","year":"2011","journal-title":"Endocrinology"},{"key":"2020071612421673700_B46","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1210\/jcem-58-5-850","article-title":"Multiple hormones stimulate the production of somatomedin by cultured human fibroblasts","volume":"58","author":"Clemmons","year":"1984","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612421673700_B47","doi-asserted-by":"crossref","first-page":"13810","DOI":"10.1016\/S0021-9258(18)80073-4","article-title":"Insulin-like growth factors (IGF) in muscle development. Expression of IGF-I, the IGF-I receptor, and an IGF binding protein during myoblast differentiation","volume":"264","author":"Tollefsen","year":"1989","journal-title":"J Biol Chem"},{"key":"2020071612421673700_B48","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1002\/jbmr.1980","article-title":"Forum on bone and skeletal muscle interactions: summary of the proceedings of an ASBMR workshop","volume":"28","author":"Bonewald","year":"2013","journal-title":"J Bone Miner Res"},{"key":"2020071612421673700_B49","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1002\/mus.880110606","article-title":"Neonatal androgen maintains sexually dimorphic muscles in the absence of innervation","volume":"11","author":"Fishman","year":"1988","journal-title":"Muscle Nerve"},{"key":"2020071612421673700_B50","doi-asserted-by":"crossref","first-page":"3376","DOI":"10.1210\/en.2012-1001","article-title":"Characterization of the spinal nucleus of the bulbocavernosus neuromuscular system in male mice lacking androgen receptor in the nervous system","volume":"153","author":"Raskin","year":"2012","journal-title":"Endocrinology"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/156\/12\/4522\/8987503\/endo4522.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/156\/12\/4522\/8987503\/endo4522.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,22]],"date-time":"2022-05-22T03:46:07Z","timestamp":1653191167000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/156\/12\/4522\/2422756"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9,22]]},"references-count":50,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2015,12,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2015-1479","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,9,22]]}}}