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Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059
Address all correspondence and requests for reprints to: Shalender Bhasin, M.D., Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059. E-mail: sbhasin{at}ucla.edu.
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Abstract |
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2 (PPAR2) mRNA and PPAR2 protein and CCAAT/enhancer binding protein 
. The number of MyoD+ myogenic cells and MHC+ myotubes and MyoD and MHC mRNA and protein levels increased dose dependently in response to testosterone and DHT treatment. Both testosterone and DHT decreased the number of adipocytes and down-regulated the expression of PPAR2 mRNA and PPAR2 protein and CCAAT/enhancer binding protein . Androgen receptor mRNA and protein levels were low at baseline but increased after testosterone or DHT treatment. The effects of testosterone and DHT on myogenesis and adipogenesis were blocked by bicalutamide. Therefore, testosterone and DHT regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor-mediated pathway. The observation that differentiation of pluripotent cells is androgen dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men. |
Introduction |
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The mechanisms by which testosterone regulates body composition are poorly understood. The prevalent view is that testosterone increases muscle mass by stimulating muscle protein synthesis (5, 16, 17, 18, 19). Indeed, testosterone administration increases nitrogen retention in castrated male rats (16), in eunuchoidal men, in women, and in boys before puberty (17). Testosterone administration to young, hypogonadal men (5) and older men with low testosterone levels stimulates muscle protein synthesis (18, 19). The protein synthesis hypothesis, however, does not explain the decrease in fat mass and the increase in myonuclear and satellite cell numbers associated with testosterone administration.
Muscle growth and regeneration during postnatal development and hypertrophy is dependent on the addition of myonuclei to muscle fibers (20, 21). Because the nuclei within the muscle fibers are post mitotic, new myonuclei must be contributed by the satellite cells (20, 21, 22). An increase in satellite cell number is an antecedent of an increase in myonuclear number and muscle fiber hypertrophy (20, 21, 22). Testosterone supplementation increases satellite cell number in the levator ani of rats (23) and the skeletal muscle of men (15). The uncommitted, pluripotent stem cells of mesodermal origin that are resident within the muscle serve as reservoirs for the generation of new satellite cells or myoblasts during muscle regeneration or hypertrophy (24) and of adipocytes in the muscle and adipose deposits throughout the body (25). To explain the reciprocal changes in fat and muscle mass and the increase in satellite cell number during testosterone administration, we hypothesized that, in addition to direct effects on protein synthesis and satellite cell replication, testosterone promotes the commitment of pluripotent precursor cells into the myogenic lineage and inhibits their differentiation into the adipogenic lineage.
To test this hypothesis, we used pluripotent, mesenchymal C3H 10T1/2 (10T1/2) cells that are capable of differentiating into muscle, fat, cartilage, and bone cells and that have been used widely as a model for studying the regulation of myogenic and adipogenic lineage determination (26, 27, 28). Commitment of 10T1/2 cells to myogenic lineage is associated with early activation of muscle-specific transcription factors, such as MyoD, myogenin, and Myf5, followed by the expression of desmin and myosin heavy chain II (MHC) in terminally differentiated cells (26, 27, 28, 29, 30, 31). Peroxisomal proliferator-activated receptor 2 (PPAR2) and CCAAT/enhancer binding protein (C/EBP) are key transcription factors necessary for adipogenic differentiation (31, 32, 33). We determined the effects of testosterone and dihydrotestosterone (DHT), two potent androgens, on the differentiation of 10T1/2 into myogenic and adipogenic lineages. We also assessed the effects of testosterone and DHT on the expression of myogenic and adipogenic differentiation markers. We evaluated whether these effects occur through an androgen receptor (AR)-mediated pathway.
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Materials and Methods |
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Immunocytochemical analyses of MHC, MyoD, and AR
Cells grown in eight-well chamber slides were fixed in 2% paraformaldehyde, quenched with H2O2, blocked with normal horse serum, and incubated with a specific antibody. Detection was based on a secondary biotinylated antibody (1:200), followed by the addition of the streptavidin-horseradish peroxidase ABC complex (1:100; Vectastain Elite ABC System, Novocastra Laboratories, Newcastle upon Tyne, UK) and 3,3'-diaminobenzidine. The cells were counterstained with Meyer’s hematoxylin. In negative controls, we either omitted the first antibody or used a rabbit nonspecific IgG.
The cytochemical staining was quantitated by densitometry using the ImagePro program (Media Cybernetics, Silver Spring, MD). The number of MyoD- and MHC-positive cells was counted against the total number of cells determined by counterstaining. The area of MHC+ cells was computed per field and averaged over 10 fields.
Oil red O staining and adipocyte counting
10T1/2 cells were washed, fixed in 2% paraformaldehyde, and stained with 0.3% Oil red O. The number of adipocytes was counted under a bright-field microscope in ten 100-X fields and averaged.
Western blot analysis
Cell lysates (50–100 µg) were subjected to Western blot analyses by 7.5% gel electrophoresis, using 1:200 mouse monoclonal anti-MHC (slow, Vector Laboratories, Inc., Burlingame, CA), 1:500 anti-AR, 1:500 anti-MyoD, 1:1000 anti-PPAR, 1:300 anti-C/EBP, or 1:10000 antiglyceraldehyde-3-phosphate dehydrogenase (GAPDH) antibody (Santa Cruz Biotechnology, Santa Cruz, CA). The washed filters were incubated with 1:1000 dilution of secondary antibodies linked to horseradish peroxidase. Immunoreactive bands were visualized by using the enhanced chemiluminescence detection system (Amersham, Chicago, IL).
RT-PCR and real-time quantitative PCR
Total RNA, extracted by using the Trizol-Reagent (Invitrogen, Carlsbad, CA), was reverse transcribed, and cDNA was amplified for 36 cycles by PCR at 94 C for 30 sec, primer annealing at 58 C for 30 sec, and extension at 72 C for 1 min. PCR products were analyzed in 2% agarose gels. The locations of the forward/reverse PCR primers are as follows: AR (187 bp) 1937-1958/2124-2102 on S56585 and GAPDH (152 bp) 606-626/758-738 on BC023196.
For real-time RT-PCR analysis of mRNA levels, forward/reverse primers were as follows: MyoD (130 bp) 801-821/930-911 on M84918 and PPAR2 (241 bp) 79-99/320-299 on BC021798. The primers for PPAR2 were specific for PPAR2 and did not detect PPAR1. The Qiagen Syber-green RT-PCR kit with HotStar Taq DNA polymerase was used (Qiagen, Valencia, CA) with the iCycler PCR thermocycler and fluorescent detector lid (Bio-Rad, Hercules, CA). The protocol included RT for 30 min at 50 C, using 250 ng (25 ng for GAPDH) RNA; melting for 15 min at 95 C; and 40 cycles of three-step PCR, including melting for 15 sec at 95 C, annealing for 30 sec at 58 C, and elongation for 30 sec at 72 C with a detection step of 15 sec at 81 C; followed by a melting curve from 55–95 C at the rate of 0.5 C per 10 sec. The inverse derivatives of melting curves showed sharp peaks for MyoD product at 88 C, PPAR2 at 83.5 C, and GAPDH at 86 C, indicating the correct products. Samples were analyzed in quadruplicate for MyoD or PPAR2 in parallel with GAPDH control; standard curves were generated by log dilutions of pMyoD and pGAPDH plasmids or PPAR2 PCR fragment from 1 fg to 1 ng. mRNA levels were calculated using the iCycler iQ software (Bio-Rad). The ratios of MyoD or PPAR2 mRNA to GAPDH mRNA were computed.
Statistical analyses
All data are presented as mean ± SEM. Between-group differences were analyzed by using ANOVA. If overall ANOVA revealed significant differences, then pair-wise comparisons between groups were performed using Tukey’s procedure. All comparisons were two-tailed, and P values less than 0.05 were considered statistically significant. The experiments were repeated two to four times, and data from representative experiments are shown.
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Results |
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). The AR mRNA and protein levels, corrected for GAPDH mRNA and protein expression, respectively, were higher in cells incubated with DHT and testosterone (data not shown) than in control cells (Fig. 1A). By immunocytochemical staining using a specific anti-AR antibody (Fig. 1B), very little staining (mostly cytoplasmic) was found in untreated control wells, and none was observed in cells that were not treated with anti-AR antibody (data not shown). Incubation with graded doses of DHT or testosterone increased nuclear AR staining (Fig. 1B shows only selective doses). Androgen stimulation of AR expression was blocked by coincubation with an AR antagonist, flutamide, suggesting that AR is involved in this autoregulation.
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shows the dose-dependent effect of testosterone (0–300 nM) treatment on the area of MHC+ myogenic cells measured by immunocytochemistry. The expression of MHC was observed mostly in multinucleated myotubes and was significantly increased in a concentration-dependent manner in cells treated with testosterone (Fig. 2A) or DHT (data not shown). In contrast, pregnenolone (200 nM), a steroid with little androgenic activity, had no significant effect on the number of MHC+ myotubes, indicating that these effects are not common to all steroid hormones. Quantitative image analysis of these MHC+ cells (Fig. 2A, lower panel) showed that treatment with graded concentrations of testosterone (0–300 nM) or DHT (0–30 nM) significantly increased the number of MHC+ myogenic cells; at the highest concentrations of testosterone and DHT, the area of MHC+ myotubes was increased 4- to 5-fold compared with control wells (mean: 135 myotubes per 103 µm2 for testosterone vs. 26 for control, P < 0.001; and 104 myotubes per 103 µm2 for DHT vs. 26 for control, P < 0.001). Western blot analysis confirmed that graded doses of testosterone dose-dependently increased MHC protein expression compared with vehicle control (Fig. 2B).
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, C and D). By real-time quantitative RT-PCR, the ratio of MyoD to GAPDH mRNA levels in cells treated with testosterone (30–300 nM) or DHT (3–30 nM; Fig. 2C) was significantly increased compared with controls. By Western blot analysis, DHT (30 nM) up-regulated MyoD protein expression by over 2-fold after normalizing for GAPDH (Fig. 2D).
Testosterone and DHT inhibit adipogenesis
10T1/2 cells were treated with testosterone or DHT for 12 d, and the number of differentiated adipocytes was counted (Fig. 3A). Testosterone and DHT each dose-dependently inhibited the number of adipocytes to approximately 50% of control at the highest androgen concentrations (mean: 18 adipocytes per x100 field for testosterone vs. 35 for controls, P = 0.0002; 18 adipocytes per x100 field for DHT vs. 33 for controls, P = 0.0002).
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). Thus, increasing testosterone (Fig. 3B) and DHT (data not shown) concentrations (0–300 nM) down-regulated the expression of PPAR2 mRNA (measured by real-time RT-PCR). DHT (Fig. 3C) and testosterone (data not shown) dose-dependently inhibited the expression of PPAR2 protein. DHT also inhibited the expression of 42- and 30-kDa C/EBP proteins in a dose-dependent manner (Fig. 3C).
Effects of testosterone and DHT on myogenesis are blocked by an AR antagonist
To determine whether the effects of testosterone and DHT on myogenesis are mediated through the AR pathway, we assessed whether these effects could be blocked by bicalutamide, a competitive AR antagonist. Incubation of cells with 30 nM testosterone or 10 nM DHT resulted in a higher MHC+ myotube area than medium alone (Fig. 4, A and B). The effects of testosterone and DHT were inhibited dose dependently by bicalutamide. The stimulation of MHC protein by testosterone and DHT, by Western blotting, was also blocked by graded concentrations of bicalutamide (Fig. 4C).
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, A and B). The stimulation of MyoD+ cell number by testosterone and DHT was blocked by 3- to 10-fold molar excess of bicalutamide.
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, A and B). By Western blot analysis, inhibition of C/EBP protein expression by DHT was reversed by bicalutamide (Fig. 6B). AR expression was up-regulated with DHT treatment, and bicalutamide inhibited basal and DHT-induced AR expression.
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Discussion |
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The anabolic effects of androgens on the skeletal muscle have been controversial for over six decades, primarily due to problems of study design (1); the nature and the reasons for this controversy have been discussed in excellent reviews (1). However, recent studies (2, 3, 4, 5, 6, 7) have demonstrated that replacement doses of testosterone, when given to hypogonadal men, increase fat-free mass and decrease fat mass. Administration of supraphysiological doses of testosterone to eugonadal men leads to further gains in fat-free mass, muscle size, and maximal voluntary strength (12). Testosterone effects on fat-free mass are directly correlated with the administered dose and the serum testosterone concentrations; in contrast, the changes in whole-body and regional fat mass are inversely correlated with testosterone dose and concentrations (13). Thus, testosterone is an important regulator of body composition in men.
The mechanisms by which testosterone regulates body composition are poorly understood. Observations that testosterone administration increases nitrogen retention in castrated male mammals (16) led to the hypothesis that testosterone increases muscle mass by stimulating muscle protein synthesis. Studies in young, hypogonadal men (5) and older men with low testosterone levels (18, 19) have reported gains in fractional muscle protein synthesis after testosterone administration. However, the hypothesis that muscle protein synthesis is the primary site of androgen action does not adequately explain either the increases in myonuclear and satellite cell number that accompany testosterone supplementation (15) or the reciprocal decrease in fat mass (13). Our hypothesis that testosterone affects body composition by regulating pluripotent cell differentiation provides a unifying explanation for the observed discordant changes in muscle and fat mass caused by testosterone supplementation. Increased commitment of pluripotent cells into the myogenic lineage would also be consistent with the observed increase in the number of satellite cells. However, it is possible that significant changes in muscle protein synthesis and/or degradation may accompany induction of myogenesis by testosterone administration. We cannot exclude the possibility that androgens might also affect additional steps in the differentiation of myogenically committed cells, such as the satellite cells.
The 10T1/2 cells are a recognized in vitro model of cell differentiation that have been used widely to define the earlier stages of myogenesis (26, 27, 28); however, no experimental model can replicate the complexity of the living human organism. Treatment with 5-azacytidine or transfection with cDNAs for MyoD or Myf5 can induce a fraction of these cells to differentiate into myogenic cells (26, 27, 28), leading to the appearance of mononuclear myoblasts (26, 27, 28). After the removal of certain key growth factors, myoblasts fuse into polynucleated myotubes that express MHC and other proteins characteristic of the differentiated muscle fibers. However, the late stages of myogenesis in which myotubes become organized into functional muscle bundles and develop innervation and vascularization are not represented in this in vitro model. Also, because of the murine fetal origin of 10T1/2 cells, we do not know whether the changes observed in these cells can be extrapolated to native pluripotent stem cells of adult humans. Although 10T1/2 cells mimic many differentiation features of the adult pluripotent stem cells and are a widely used model for studying the regulation of stem-cell commitment to myogenesis or adipogenesis, it would be premature to apply these data directly to human myogenesis. Further studies are needed to confirm the effects of androgens on native, adult, pluripotent stem cells.
Although there is now agreement that testosterone administration increases muscle mass in men, the effects of androgen administration on fat mass are not as well recognized. Androgens inhibit whole-body fat mass; thus, androgen deficiency in men is associated with higher fat mass compared with eugonadal controls (3), and testosterone supplementation decreases whole-body and intermuscular fat mass (6, 7, 8, 9). De Pergola (36) has reported that testosterone inhibits differentiation of adipocyte precursor cells, suppresses lipid uptake and lipoprotein lipase activity in adipocytes, and up-regulates the number of ß-adrenergic receptors. In our study, the expression of the markers of adipogenic differentiation, such as PPAR2 and C/EBP, was down-regulated, and the number of adipocytes was inhibited in a dose-dependent manner by both testosterone and DHT. Our data are consistent with those of James et al., (37) who observed a significant decrease in the number of fat cells in the inguinal and retroperitoneal region of female rats treated with supraphysiological doses of testosterone. Taken together, these data suggest that androgens inhibit adipogenic commitment of mesenchymal pluripotent cells, resulting in the formation of fewer adipocytes. However, we do not know whether androgens have additional effects on preadipocyte differentiation because C3H 10T1/2 cells are not an optimum model of preadipocyte differentiation.
The androgen effects on both myogenic and adipogenic differentiation were blocked by bicalutamide, indicating that these effects are mediated through an AR-mediated pathway. It has been speculated that the anabolic effects of supraphysiological doses of androgens might represent an antiglucocorticoid effect; our data do not exclude this possibility. However, almost complete inhibition of the effects of both testosterone and DHT by bicalutamide is consistent with an important role of the AR pathway in mediating these effects on 10T1/2 cell differentiation.
Although both testosterone and DHT were effective in stimulating myogenesis and inhibiting adipogenesis, DHT was more potent than testosterone in this model. These data confirm previous observations that suggest that DHT is more potent than testosterone in some androgen-responsive tissues (34). Pregnenolone, a steroid precursor of testosterone, had no significant effect on the differentiation of 10T1/2 cells, indicating that these effects are specific to androgenic steroids.
Significant effects of testosterone and DHT on pluripotent cell differentiation were observed at concentrations that bracket the circulating levels of these hormones in young men. However, incubation with testosterone and DHT concentrations that were higher than the upper limit of the normal male range was associated with greater stimulation of myogenesis and greater inhibition of adipogenesis than with physiological concentrations.
Under basal conditions, 10T1/2 cells expressed AR mRNA and protein in low abundance, and testosterone and DHT up-regulated the expression of AR mRNA and protein in these cells. The up-regulation of AR by androgens may provide a mechanism for potentiation of androgen responsiveness. Ferrando et al. (18) have also reported an increase in AR expression in the skeletal muscle of men after androgen administration.
In this in vitro model, we did not find a complete concordance in the magnitude of changes in the mRNA and protein concentrations of myogenic markers and the change in the number of MHC+ myotubes. We only studied a limited number of time points, and it is possible that the time course for the optimal induction of different myogenic markers is different from that of myotube formation. Therefore, it is not surprising that the changes in steady-state concentrations of mRNA and protein concentrations do not always show complete proportionality to phenotypic changes observed at a specific time point in cell differentiation.
These data do not exclude the possibility that androgens might have additional effects on muscle protein synthesis, satellite cell replication, myoblast fusion, myogenic progression to fully differentiated fibers, and one or more steps in the adipogenic differentiation pathway. However, the reciprocal effects of androgens on myogenic and adipogenic differentiation suggest that these hormones likely act at sites that are proximal to both the myogenic and adipogenic differentiation pathways and involve mechanisms for lineage determination in mesenchymal precursor cells. The molecular mechanisms by which androgens regulate lineage commitment are unknown. Previous studies have suggested that the Wnt signaling pathway plays an important role in lineage determination in pluripotent stem cells (32, 35). Further studies are needed to determine the role of Wnt and other signaling pathways in mediating androgen action on pluripotent stem-cell differentiation.
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Acknowledgments |
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Footnotes |
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R.S., J.N.A., and W.E.T. contributed equally to this work as first authors.
N.F.G.-C. and S.B. contributed equally.
Abbreviations: AR, Androgen receptor; C/EBP, CCAAT/enhancer binding protein ; DHT, dihydrotestosterone; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MHC, myosin heavy chain II; PPAR2, peroxisomal proliferator-activated receptor 2.
Received June 12, 2003.
Accepted for publication July 14, 2003.
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J. N. Artaza, S. Bhasin, T. R. Magee, S. Reisz-Porszasz, R. Shen, N. P. Groome, M. M. Fareez, and N. F. Gonzalez-Cadavid Myostatin Inhibits Myogenesis and Promotes Adipogenesis in C3H 10T(1/2) Mesenchymal Multipotent Cells Endocrinology, August 1, 2005; 146(8): 3547 - 3557. [Abstract] [Full Text] [PDF]
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Y. Chen, J. D Zajac, and H. E MacLean Androgen regulation of satellite cell function J. Endocrinol., July 1, 2005; 186(1): 21 - 31. [Abstract] [Full Text] [PDF]
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 C. J. Lengner, M. Q. Hassan, R. W. Serra, C. Lepper, A. J. van Wijnen, J. L. Stein, J. B. Lian, and G. S. Stein Nkx3.2-mediated Repression of Runx2 Promotes Chondrogenic Differentiation J. Biol. Chem., April 22, 2005; 280(16): 15872 - 15879. [Abstract] [Full Text] [PDF]
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A. M. Traish, P. Toselli, S.-J. Jeong, and N. N. Kim Adipocyte Accumulation in Penile Corpus Cavernosum of the Orchiectomized Rabbit: A Potential Mechanism for Veno-occlusive Dysfunction in Androgen Deficiency J Androl, March 1, 2005; 26(2): 242 - 248. [Abstract] [Full Text] [PDF]
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R. Jasuja, P. Ramaraj, R. P. Mac, A. B. Singh, T. W. Storer, J. Artaza, A. Miller, R. Singh, W. E. Taylor, M. L. Lee, et al. {Delta}-4-Androstene-3,17-Dione Binds Androgen Receptor, Promotes Myogenesis in Vitro, and Increases Serum Testosterone Levels, Fat-Free Mass, and Muscle Strength in Hypogonadal Men J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 855 - 863. [Abstract] [Full Text] [PDF]
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S. Bhasin, L. Woodhouse, R. Casaburi, A. B. Singh, R. P. Mac, M. Lee, K. E. Yarasheski, I. Sinha-Hikim, C. Dzekov, J. Dzekov, et al. Older Men Are as Responsive as Young Men to the Anabolic Effects of Graded Doses of Testosterone on the Skeletal Muscle J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 678 - 688. [Abstract] [Full Text] [PDF]
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S. T. Page, K. L. Herbst, J. K. Amory, A. D. Coviello, B. D. Anawalt, A. M. Matsumoto, and W. J. Bremner Testosterone Administration Suppresses Adiponectin Levels in Men J Androl, January 1, 2005; 26(1): 85 - 92. [Abstract] [Full Text] [PDF]
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M. Quinkler, B. Sinha, J. W Tomlinson, I. J Bujalska, P. M Stewart, and W. Arlt Androgen generation in adipose tissue in women with simple obesity - a site-specific role for 17{beta}-hydroxysteroid dehydrogenase type 5 J. Endocrinol., November 1, 2004; 183(2): 331 - 342. [Abstract] [Full Text] [PDF]
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E. T. Schroeder, L. Zheng, M. D. Ong, C. Martinez, C. Flores, Y. Stewart, C. Azen, and F. R. Sattler Effects of Androgen Therapy on Adipose Tissue and Metabolism in Older Men J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4863 - 4872. [Abstract] [Full Text] [PDF]
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I. Sinha-Hikim, W. E. Taylor, N. F. Gonzalez-Cadavid, W. Zheng, and S. Bhasin Androgen Receptor in Human Skeletal Muscle and Cultured Muscle Satellite Cells: Up-Regulation by Androgen Treatment J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5245 - 5255. [Abstract] [Full Text] [PDF]
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L. J. Woodhouse, N. Gupta, M. Bhasin, A. B. Singh, R. Ross, J. Phillips, and S. Bhasin Dose-Dependent Effects of Testosterone on Regional Adipose Tissue Distribution in Healthy Young Men J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 718 - 726. [Abstract] [Full Text] [PDF]
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