Abstract
Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical function. Together, these findings suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia.
Highlights
Androgens have wide variety of physiological actions including promotion of growth hormone release, stimulation of appetite, anabolic action, stimulus effect on the central nerve system, and regulation of energy homeostasis
We evaluated cofactor recruitment to androgen receptor (AR) by M2H with 15 cofactors; prostate-derived Ets factor (PDEF), filamin A, alpha (FLNA), p21-activated kinase 6 (PAK6), TBP-associated factor 250 kD (TAFII250), protein inhibitor of activated STAT1 (PIAS1), protein inhibitor of activated STAT 3 (PIAS3), protein inhibitor of activated STAT y (PIASy), proline-rich nuclear receptor coactivator 2 (PNRC2), nuclear receptor subfamily 2, group C, member 2NR2C2 (TR4), steroid receptor coactivator 3 (SRC3), receptor of activated protein kinase C 1 (RACK1), steroid receptor coactivator 1 (SRC1), four and a half LIM domains 2 (FHL2), mothers against decapentaplegic homolog 3 (Smad3), and cytochrome co-oxidase subunit Vb (COX5B)
The concentration in prostate was higher than that in the levator ani muscle, indicating that tissue distribution does not account for the tissue specific effect of selective androgen receptor modulators (SARMs)-2f
Summary
Androgens have wide variety of physiological actions including promotion of growth hormone release, stimulation of appetite, anabolic action, stimulus effect on the central nerve system, and regulation of energy homeostasis. Testosterone replacement therapy is effective for recovery of muscle mass and function in patients with sarcopenia or cancer cachexia [8, 9]. Selective androgen receptor modulators (SARMs) have been intensively investigated for possible application in diseases with muscular weakness, to date no SARM compounds have been launched as therapeutic agents for sarcopenia or cachexia [18]. We previously reported that a SARM compound, SARM-2f, selectively binds to androgen receptor (AR), stimulates AR transcriptional activity, and exerts an anabolic effect on skeletal muscles such as the levator ani muscle, soleus muscle, and gastrocnemius muscle in rat Hershberger assays and cancer cachexia models [19, 20]. Our findings of tissue-specific AR modulation by SARM-2f and of SARM-2f-mediated physical function improvements suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia
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