Abstract
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.
Highlights
Testosterone’s anabolic effects on the skeletal muscle are widely recognized (Bhasin et al, 2006)
Testosterone levels in men are positively associated with skeletal muscle mass, strength, and physical function (Roy et al, 2002; Orwoll et al, 2006)
We show here that the administration of recombinant follistatin increased muscle mass, as expected (Lee, 2007; Kota et al, 2009; Singh et al, 2009; Dalton et al, 2011; Braga et al, 2012), but surprisingly, unlike testosterone, rFst did not affect prostate mass
Summary
Testosterone’s anabolic effects on the skeletal muscle are widely recognized (Bhasin et al, 2006). Testosterone levels in men are positively associated with skeletal muscle mass, strength, and physical function (Roy et al, 2002; Orwoll et al, 2006). Consistent with these epidemiological correlations, testosterone administration increases lean body mass and maximal voluntary strength in men (Bhasin et al, 1996; Bhasin et al, 1997; Snyder et al, 1999; Wang et al, 2000; Page et al, 2005; Srinivas-Shankar et al, 2010). Concerns about the potential prostatic side effects of testosterone have limited enthusiasm for testosterone’s applications as a function-promoting anabolic therapy in older men (Bhasin et al, 2006; Calof et al, 2005). We report a novel strategy for achieving the selectivity of testosterone’s anabolic actions on skeletal muscle while sparing the prostate
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