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

被引:44
作者
Dubois, Vanessa [1 ]
Simitsidellis, Ioannis [4 ]
Laurent, Michael R. [1 ,2 ]
Jardi, Ferran [3 ]
Saunders, Philippa T. K. [4 ]
Vanderschueren, Dirk [3 ]
Claessens, Frank [1 ]
机构
[1] Katholieke Univ Leuven, Mol Endocrinol Lab, Dept Cellular & Mol Med, B-3000 Leuven, Belgium
[2] Katholieke Univ Leuven, Dept Gerontol & Geriatr, B-3000 Leuven, Belgium
[3] Katholieke Univ Leuven, Clin & Expt Endocrinol, Dept Clin & Expt Med, B-3000 Leuven, Belgium
[4] Univ Edinburgh, Med Res Council Ctr Inflammat Res, Edinburgh EH16 4SB, Midlothian, Scotland
基金
英国医学研究理事会;
关键词
CONNECTIVE-TISSUE FIBROBLASTS; IGF-I; NEUROMUSCULAR-JUNCTION; PHYSICAL FUNCTION; BODY-COMPOSITION; SPINAL NUCLEUS; DOUBLE-BLIND; MALE-MICE; STRENGTH; BONE;
D O I
10.1210/en.2015-1479
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:4522 / 4533
页数:12
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