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Androgen effects are mediated by androgen receptor which is highly expressed in spinal motor neurons and skeletal muscles. To clarify the role of androgen receptors in ALS, we therefore examined the effect of androgen receptor antagonism in the SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      The androgen receptor antagonist, flutamide, was administered to presymptomatic SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      mice as a slow\u2010release subcutaneous implant (5\u00a0mg\u00b7day\n                      <jats:sup>\u22121<\/jats:sup>\n                      ). Testosterone, flutamide, and metabolite levels were measured in blood and spinal cord tissue by LC\u2013MS\u2013MS. Effects on disease onset and progression were assessed using motor function tests, survival, muscle, and neuropathological analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Flutamide was metabolised to 2\u2010hydroxyflutamide achieving steady\u2010state plasma levels across the study duration and reached the spinal cord at pharmacologically active concentrations. Flutamide treatment accelerated disease onset and locomotor dysfunction in male SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      mice, but not female mice, without affecting survival. Analysis of hindlimb muscles revealed exacerbation of myofibre atrophy in male SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      mice treated with flutamide, although motor neuron pathology was not affected.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>\n                      The androgen receptor antagonist accelerated disease onset in male SOD1\n                      <jats:sup>G93A<\/jats:sup>\n                      mice, leading to exacerbated muscle pathology, consistent with a role of androgens in modulating disease severity, sexual dimorphism, and peripheral pathology in ALS. These results also demonstrate a key contribution of skeletal muscle pathology to disease onset, but not outcome, in this mouse model of ALS.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.14657","type":"journal-article","created":{"date-parts":[[2019,3,8]],"date-time":"2019-03-08T14:33:21Z","timestamp":1552055601000},"page":"2111-2130","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Androgen receptor antagonism accelerates disease onset in the SOD1\n                    <sup>G93A<\/sup>\n                    mouse model of amyotrophic lateral sclerosis"],"prefix":"10.1111","volume":"176","author":[{"given":"Victoria M.","family":"McLeod","sequence":"first","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chew L.","family":"Lau","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew D.F.","family":"Chiam","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health University of Melbourne  Parkville VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thusitha W.","family":"Rupasinghe","sequence":"additional","affiliation":[{"name":"Metabolomics Australia, School of BioSciences University of Melbourne  Melbourne VIC Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Roessner","sequence":"additional","affiliation":[{"name":"Metabolomics Australia, School of BioSciences University of Melbourne  Melbourne VIC 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