title: Enobosarm (GTx-024) Modulates Adult Skeletal Muscle Mass Independently of the Androgen Receptor in the Satellite Cell Lineage.
abstract: 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.
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Cellular and Molecular Medicine, Department of Gerontology and Geriatrics (M.R.L.), and Clinical and Experimental Endocrinology (F.J., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium; and Medical Research Council Centre for Inflammation Research (I.S., P.T.K.S.), University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dubois
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Cellular and Molecular Medicine, Department of Gerontology and Geriatrics (M.R.L.), and Clinical and Experimental Endocrinology (F.J., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium; and Medical Research Council Centre for Inflammation Research (I.S., P.T.K.S.), University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Simitsidellis
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Cellular and Molecular Medicine, Department of Gerontology and Geriatrics (M.R.L.), and Clinical and Experimental Endocrinology (F.J., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium; and Medical Research Council Centre for Inflammation Research (I.S., P.T.K.S.), University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Michaël R
authors.initials: MR
authors.lastname: Laurent
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Cellular and Molecular Medicine, Department of Gerontology and Geriatrics (M.R.L.), and Clinical and Experimental Endocrinology (F.J., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium; and Medical Research Council Centre for Inflammation Research (I.S., P.T.K.S.), University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Ferran
authors.initials: F
authors.lastname: Jardi
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Cellular and Molecular Medicine, Department of Gerontology and Geriatrics (M.R.L.), and Clinical and Experimental Endocrinology (F.J., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium; and Medical Research Council Centre for Inflammation Research (I.S., P.T.K.S.), University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Cellular and Molecular Medicine, Department of Gerontology and Geriatrics (M.R.L.), and Clinical and Experimental Endocrinology (F.J., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium; and Medical Research Council Centre for Inflammation Research (I.S., P.T.K.S.), University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Dirk
authors.initials: D
authors.lastname: Vanderschueren
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., F.C.), Department of Cellular and Molecular Medicine, Department of Gerontology and Geriatrics (M.R.L.), and Clinical and Experimental Endocrinology (F.J., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium; and Medical Research Council Centre for Inflammation Research (I.S., P.T.K.S.), University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
mesh_terms: D000577:Amides / Q000494:pharmacology*; D045930:Anabolic Agents / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology; D000813:Anilides; D000818:Animals; D001823:Body Composition / Q000187:drug effects*; D002100:Cachexia / Q000188:drug therapy; D019070:Cell Lineage; D013196:Dihydrotestosterone / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D055948:Sarcopenia / Q000188:drug therapy; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects* / Q000378:metabolism; D019282:Wasting Syndrome / Q000188:drug therapy
chemical_list: D000577:Amides; D045930:Anabolic Agents; D000728:Androgens; D000813:Anilides; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; C547106:ostarine