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

Endocrinology ◽  
2015 ◽  
Vol 156 (12) ◽  
pp. 4522-4533 ◽  
Author(s):  
Vanessa Dubois ◽  
Ioannis Simitsidellis ◽  
Michaël R. Laurent ◽  
Ferran Jardi ◽  
Philippa T. K. Saunders ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Androgen Receptor ◽  
Satellite Cell ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Cell Lineage ◽  
Levator Ani ◽  
Levator Ani Muscle ◽  
Adult Skeletal Muscle ◽  
Receptor Modulator

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.

Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles

1999 ◽  
Vol 87 (6) ◽  
pp. 2016-2019 ◽  
Author(s):  
Jose Antonio ◽  
Jean D. Wilson ◽  
Fredrick W. George
Keyword(s):  
Skeletal Muscle ◽  
Androgen Receptor ◽  
Muscle Mass ◽  
Skeletal Muscles ◽  
Skeletal Muscle Mass ◽  
Levator Ani ◽  
Male Rats ◽  
Levator Ani Muscle ◽  
Plantaris Muscle ◽  
Androgen Treatment

The effects of castration and dihydrotestosterone (DHT) treatment on levels of skeletal muscle androgen receptor (AR) were examined in three groups of adult male rats: 1) intact normal rats, 2) rats castrated at 16 wk of age, and 3) rats castrated at 16 wk of age and given DHT for 1 wk starting at week 17. All animals were killed at 18 wk of age. Castration caused a decrease ( P< 0.05) in the weights of the levator ani and bulbocavernosus muscles. The administration of DHT to the castrated rats increased ( P < 0.05) the weights of the levator ani and bulbocavernosus muscles. Castration caused a significant downregulation of AR levels in the bulbocavernosus ( P< 0.05) but had no significant effect on AR levels in the levator ani muscle. DHT administration to the castrated group upregulated AR levels in the bulbocavernosus and levator ani muscles. The plantaris muscle did not significantly ( P > 0.05) change for any of the treatments. These findings suggest that the effects of castration and androgen replacement differentially affect skeletal muscle mass and AR levels.

scholarly journals Selective Androgen Receptor Modulator Treatment Improves Muscle Strength and Body Composition and Prevents Bone Loss in Orchidectomized Rats

Endocrinology ◽  
2005 ◽  
Vol 146 (11) ◽  
pp. 4887-4897 ◽  
Author(s):  
Wenqing Gao ◽  
Peter J. Reiser ◽  
Christopher C. Coss ◽  
Mitch A. Phelps ◽  
Jeffrey D. Kearbey ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Androgen Receptor ◽  
Muscle Mass ◽  
Male Rats ◽  
Levator Ani Muscle ◽  
Dependent Manner ◽  
Agonist Activity ◽  
Mineral Density ◽  
Selective Androgen Receptor Modulator ◽  
Receptor Modulator

The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights moire than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.

scholarly journals Inducible Activation of Akt Increases Skeletal Muscle Mass and Force Without Satellite Cell Activation

2010 ◽  
Vol 98 (3) ◽  
pp. 153a ◽  
Author(s):  
Bert Blaauw ◽  
Canato Marta ◽  
Lisa Agatea ◽  
Luana Toniolo ◽  
Cristina Mammucari ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Cell Activation ◽  
Satellite Cell Activation ◽  
Inducible Activation

scholarly journals Proteome-wide muscle protein fractional synthesis rates predict muscle mass gain in response to a selective androgen receptor modulator in rats

2016 ◽  
Vol 310 (6) ◽  
pp. E405-E417 ◽  
Author(s):  
Mahalakshmi Shankaran ◽  
Todd W. Shearer ◽  
Stephen A. Stimpson ◽  
Scott M. Turner ◽  
Chelsea King ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Androgen Receptor ◽  
Muscle Mass ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Synthesis Rate ◽  
Muscle Proteins ◽  
Receptor Modulator ◽  
Fractional Synthesis

Biomarkers of muscle protein synthesis rate could provide early data demonstrating anabolic efficacy for treating muscle-wasting conditions. Androgenic therapies have been shown to increase muscle mass primarily by increasing the rate of muscle protein synthesis. We hypothesized that the synthesis rate of large numbers of individual muscle proteins could serve as early response biomarkers and potentially treatment-specific signaling for predicting the effect of anabolic treatments on muscle mass. Utilizing selective androgen receptor modulator (SARM) treatment in the ovariectomized (OVX) rat, we applied an unbiased, dynamic proteomics approach to measure the fractional synthesis rates (FSR) of 167–201 individual skeletal muscle proteins in triceps, EDL, and soleus. OVX rats treated with a SARM molecule (GSK212A at 0.1, 0.3, or 1 mg/kg) for 10 or 28 days showed significant, dose-related increases in body weight, lean body mass, and individual triceps but not EDL or soleus weights. Thirty-four out of the 94 proteins measured from the triceps of all rats exhibited a significant, dose-related increase in FSR after 10 days of SARM treatment. For several cytoplasmic proteins, including carbonic anhydrase 3, creatine kinase M-type (CK-M), pyruvate kinase, and aldolase-A, a change in 10-day FSR was strongly correlated ( r2 = 0.90–0.99) to the 28-day change in lean body mass and triceps weight gains, suggesting a noninvasive measurement of SARM effects. In summary, FSR of multiple muscle proteins measured by dynamics of moderate- to high-abundance proteins provides early biomarkers of the anabolic response of skeletal muscle to SARM.

scholarly journals eIF3f depletion impedes mouse embryonic development, reduces adult skeletal muscle mass and amplifies muscle loss during disuse

2019 ◽  
Vol 597 (12) ◽  
pp. 3107-3131 ◽  
Author(s):  
Aurélie Docquier ◽  
Laura Pavlin ◽  
Audrey Raibon ◽  
Christelle Bertrand‐Gaday ◽  
Chamroeun Sar ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Embryonic Development ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Muscle Loss ◽  
Adult Skeletal Muscle

scholarly journals Preclinical Characterization of a (S)-N-(4-Cyano-3-Trifluoromethyl-Phenyl)-3-(3-Fluoro, 4-Chlorophenoxy)-2-Hydroxy-2-Methyl-Propanamide: A Selective Androgen Receptor Modulator for Hormonal Male Contraception

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 385-395 ◽  
Author(s):  
Amanda Jones ◽  
Jiyun Chen ◽  
Dong Jin Hwang ◽  
Duane D. Miller ◽  
James T. Dalton
Keyword(s):  
Androgen Receptor ◽  
Levator Ani ◽  
Male Rats ◽  
Male Contraception ◽  
Levator Ani Muscle ◽  
Dependent Manner ◽  
Mineral Density ◽  
Intact Male ◽  
Selective Androgen Receptor Modulator ◽  
Receptor Modulator

The pharmacologic effects of (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) were characterized in male rats as an animal model of hormonal male contraception. S-23 showed high binding affinity (inhibitory constant = 1.7 ± 0.2 nm) and was identified as a full agonist in vitro. In castrated male rats, the ED50 of S-23 in the prostate and levator ani muscle was 0.43 and 0.079 mg/d, respectively. In intact male rats treated for 14 d, S-23 alone suppressed LH levels by greater than 50% at doses greater than 0.1 mg/d, with corresponding decreases in the size of the prostate but increases in the size of levator ani muscle. In intact male rats treated for up to 10 wk with S-23 and estradiol benzoate (EB; necessary to maintain sexual behavior in rats), S-23 showed biphasic effects on androgenic tissues and spermatogenesis by suppressing serum concentrations of LH and FSH. EB alone showed no effect on spermatogenesis. In the EB + S-23 (0.1 mg/d) group, four of six animals showed no sperm in the testis and zero pregnancies (none of six) in mating trials. After termination of treatment, infertility was fully reversible, with a 100% pregnancy rate observed after 100 d of recovery. S-23 increased bone mineral density and lean mass but reduced fat mass in a dose-dependent manner. This is the first study to show that a selective androgen receptor modulator combined with EB is an effective and reversible regimen for hormonal male contraception in rats. The beneficial effects of S-23 on the muscle, tissue selectivity, and favorable pharmacokinetic properties make it a strong candidate for use in oral male contraception. An aryl-propionamide selective androgen receptor modulator (S-23) is an effective and reversible agent for hormonal male contraception in rats.

Inducible activation of Akt increases skeletal muscle mass and force without satellite cell activation

2009 ◽  
Vol 23 (11) ◽  
pp. 3896-3905 ◽  
Author(s):  
Bert Blaauw ◽  
Marta Canato ◽  
Lisa Agatea ◽  
Luana Toniolo ◽  
Cristina Mammucari ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Cell Activation ◽  
Satellite Cell Activation ◽  
Inducible Activation

Altered expression of genes regulating skeletal muscle mass in the portacaval anastamosis rat

2007 ◽  
Vol 292 (4) ◽  
pp. G1105-G1113 ◽  
Author(s):  
Srinivasan Dasarathy ◽  
Sean Muc ◽  
Kola Hisamuddin ◽  
John M. Edmison ◽  
Milan Dodig ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cell ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Cell Function ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Igf I ◽  
Ubiquitin Proteasome ◽  
Forelimb Grip Strength

We examined the temporal relationship between portacaval anastamosis (PCA), weight gain, changes in skeletal muscle mass and molecular markers of protein synthesis, protein breakdown, and satellite cell proliferation and differentiation. Male Sprague-Dawley rats with end to side PCA ( n = 24) were compared with sham-operated pair-fed rats ( n = 24). Whole body weight, lean body mass, and forelimb grip strength were determined at weekly intervals. The skeletal muscle expression of the ubiquitin proteasome system, myostatin, its receptor (the activin 2B receptor) and its signal, cyclin-dependant kinase inhibitor (CDKI) p21, insulin-like growth factor (IGF)-I and its receptor (IGF-I receptor-α), and markers of satellite cell proliferation and differentiation were quantified. PCA rats did not gain body weight and had lower lean body mass, forelimb grip strength, and gastrocnemius muscle weight. The skeletal muscle expression of the mRNA of ubiquitin proteasome components was higher in PCA rats in the first 2 wk followed by a lower expression in the subsequent 2 wk ( P < 0.01). The mRNA and protein of myostatin, activin 2B receptor, and CDKI p21 were higher, whereas IGF-I and its receptor as well as markers of satellite cell function (proliferating nuclear cell antigen, myoD, myf5, and myogenin) were lower at weeks 3 and 4 following PCA ( P < 0.05). We conclude that PCA resulted in uninhibited proteolysis in the initial 2 wk. This was followed by an adaptive response in the later 2 wk consisting of an increased expression of myostatin that may have contributed to reduced muscle protein synthesis, impaired satellite cell function, and lower skeletal muscle mass.

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