Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate‐sparing anabolic therapy

Aging Cell

Ravi Jasuja¹  James C. Costello²  Rajan Singh³  Vandana Gupta¹  Catherine S. Spina²  Gianluca Toraldo¹  Hyeran Jang¹  Hu Li²  Carlo Serra¹  Wen Guo¹  Pratibha Chauhan¹  Navjot S. Narula¹  Tyler Guarneri¹  Ayla Ergun²  Thomas G. Travison¹  James J. Collins² 

[1] 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, Boston, MA, USA;Howards Hughes Medical Institute, Center for BioDynamics, Boston University, Boston, MA, USA;Division of Endocrinology and Metabolism, Charles Drew University of Medicine and Science, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

关键词: aging;    anti‐aging;    sarcopenia;    sex hormones;    skeletal muscle;    steroids;   

DOI  :  10.1111/acel.12174

来源: Wiley

【 摘 要 】

Summary

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.

【 授权许可】

CC BY   
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.