Enobosarm (GTx-024) Modulates Adult Skeletal Muscle Mass Independently of the Androgen Receptor in the Satellite Cell Lineage

Endocrinology. 2015 Dec;156(12):4522-33. doi: 10.1210/en.2015-1479. Epub 2015 Sep 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology*
  • Anabolic Agents / pharmacology*
  • Androgens / pharmacology
  • Anilides
  • Animals
  • Body Composition / drug effects*
  • Cachexia / drug therapy
  • Cell Lineage
  • Dihydrotestosterone / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Orchiectomy
  • Organ Size / drug effects
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Sarcopenia / drug therapy
  • Satellite Cells, Skeletal Muscle / drug effects*
  • Satellite Cells, Skeletal Muscle / metabolism
  • Wasting Syndrome / drug therapy


  • Amides
  • Anabolic Agents
  • Androgens
  • Anilides
  • Receptors, Androgen
  • Dihydrotestosterone
  • ostarine