Jasuja Ravi, Costello James C, Singh Rajan, Gupta Vandana, Spina Catherine S, Toraldo Gianluca, Jang Hyeran, Li Hu, Serra Carlo, Guo Wen, Chauhan Pratibha, Narula Navjot S, Guarneri Tyler, Ergun Ayla, Travison Thomas G, Collins James J, Bhasin Shalender
Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.
Aging Cell. 2014 Apr;13(2):303-10. doi: 10.1111/acel.12174. Epub 2013 Dec 4.
Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone's adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone's promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without α-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone's effects on prostate, but did not affect testosterone's anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy.
由于睾酮对肌肉具有合成代谢作用，目前正在探索将其作为一种功能促进型合成代谢疗法，用于治疗与衰老相关的功能受限；然而，对睾酮对前列腺不良影响的担忧促使人们努力开发能够选择性增加肌肉量同时保护前列腺的策略。睾酮的促肌生成作用是通过上调卵泡抑素来介导的。我们在此表明，给予重组卵泡抑素（rFst）可增加小鼠的肌肉量，但对前列腺重量没有影响。与给予rFst的结果一致，卵泡抑素水平持续升高的卵泡抑素转基因小鼠比对照小鼠表现出更大的肌肉量，但前列腺重量相似。为了阐明睾酮和rFst在前列腺和肌肉中差异调节的信号通路，我们对用赋形剂、睾酮或rFst处理的去势雄性小鼠的前列腺和提肛肌中的mRNA进行了微阵列分析。睾酮和rFst共同调节提肛肌中的许多转录本；然而，在前列腺中，睾酮处理后几种生长促进途径中的593个转录本差异表达，而rFst的影响可忽略不计，只有9个转录本差异表达。在前列腺中对睾酮有差异反应的途径中，我们确定鸟氨酸脱羧酶（Odc1），一种多胺生物合成中的酶，是一个对睾酮有反应但对rFst无反应的基因。因此，我们对去势小鼠给予有或没有α-二氟甲基鸟氨酸（DFMO）（一种Odc1抑制剂）的睾酮。DFMO选择性地阻断了睾酮对前列腺的作用，但不影响睾酮对肌肉的合成代谢作用。睾酮与Odc1抑制剂联合给药为保留前列腺的合成代谢疗法提供了一种新的治疗策略。
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