Characterisation of the pharmacological profile of desoxymethyltestosterone (Madol), a steroid misused for doping

Diel, Patrick; Friedel, Angelika; Geyer, Hans; Kamber, Matthias; Laudenbach-Leschowsky, U.; Schänzer, W.; Thevis, Mario; Vollmer, Günter; Zierau, Oliver

doi:10.1016/j.toxlet.2006.12.004

Cited by 39 publications

(20 citation statements)

References 14 publications

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“…Nevertheless, the effects of androgens on myostatin expression are discussed controversially. On the one hand, the observed stimulation of myostatin expression by DHT and THG is in agreement with recent findings from our laboratory demonstrating an increase in myostatin expression in the rat gastrocnemius muscle after treatment with testosterone and anabolic steroids (Diel et al 2007). On the other hand, there are reports describing a downregulation of myostatin by androgens in the levator ani muscle (Mendler et al 2007).…”

Section: Discussionsupporting

confidence: 93%

“…Androgens and anabolic steroids stimulate the proliferation of C2C12 cells, accelerate the process of differentiation toward myotubes, and stimulate the expression of myostatin in undifferentiated and differentiated cells. Our observation that androgens stimulate myostatin expression in C2C12 cells is supported by recent findings also demonstrating a stimulation of myostatin expression in vivo (Diel et al 2007). Anabolic steroids and inhibition of myostatin expression have been shown to increase the muscle mass.…”

Section: Discussionsupporting

confidence: 89%

“…Our recent observation that androgens and anabolic steroids modulate myostatin expression in rat skeletal muscle (Diel et al 2007) provides evidence that both act synergistically to control skeletal muscle homeostasis. To prove this hypothesis and to elucidate the molecular mechanisms involved in the control of satellite cell activity by androgens and myostatin, we have analyzed the effects of androgens and anabolic steroids on C2C12 cell proliferation and differentiation.…”

Section: Introductionmentioning

confidence: 90%

“…Recently, we demonstrated that myostatin mRNA expression is regulated by androgens in rat skeletal muscle (Diel et al 2007). To verify these in vivo results, the effects of androgens on myostatin expression during C2C12 cell differentiation were studied in the present study.…”

Section: Effects Of Androgens On the Expression Of Myostatin During Mmentioning

confidence: 99%

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C2C12 myoblastoma cell differentiation and proliferation is stimulated by androgens and associated with a modulation of myostatin and Pax7 expression

Diel¹,

Baadners²,

Schlüpmann³

et al. 2008

Journal of Molecular Endocrinology

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Androgens are modulators of skeletal muscle adaptation and regeneration processes. The control of satellite cell activity is a key mechanism during this process. In this study, we analyzed the ability of dihydrotestosterone (DHT) and anabolic steroids to induce and modulate the differentiation of C2C12 myoblastoma cells toward myotubes. C2C12 cells were dose-dependently treated with DHT and anabolic steroids. The time-dependent effects on differentiation were measured and correlated with the expression of genes involved in the regulation of satellite cell activity. The distribution of C2C12 cells within the cell cycle was measured by flow cytometry and differentiation by creatine kinase (CK) activity. Gene expression was analyzed using quantitative real-time PCR and confocal microscopy. The treatment with DHT and anabolic steroids resulted in a stimulation of C2C12 cell proliferation and CK activity. The antiandrogen flutamide was able to antagonize this effect. The expression of the androgen receptor, SOX8, SOX9, Delta, Notch, myostatin, and paired box gene7 (Pax7) was modulated by androgens. The treatment with DHT and anabolic steroids resulted in a strong stimulation of myostatin expression not only in undifferentiated cells but also in myotubes. The stimulation could be antagonized by flutamide. The expression of Pax7 was detectable in C2C12 cells early after treatment with DHT. Our results demonstrate that the key mechanisms of satellite cell differentiation are modulated by androgens. Androgens stimulate the proliferation of C2C12 cells, accelerate the process of differentiation, and increase the expression of myostatin in undifferentiated and differentiated cells. Our findings may have implications not only for the treatment of muscular diseases but also for the improvement of doping analytical methods.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 90%

Section: Effects Of Androgens On the Expression Of Myostatin During Mmentioning

confidence: 99%

See 2 more Smart Citations

C2C12 myoblastoma cell differentiation and proliferation is stimulated by androgens and associated with a modulation of myostatin and Pax7 expression

Diel¹,

Baadners²,

Schlüpmann³

et al. 2008

Journal of Molecular Endocrinology

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“…The COUP-TFII-overexpressing cell lines in the current study demonstrated regulation of caveolin-3 and Akt-1, Smad 2 and 4, myostatin, myostatin receptor ACVR2A, glucocorticoid receptor (GR), and AR, genes that have interconnecting roles in regulation of differentiation and hypertrophy (4,7,9,10,14,15,16,17,19,23,32,39,40,41,43,44,47,48,52,56,71,76).…”

Section: Discussionmentioning

confidence: 69%

Chicken ovalbumin upstream promoter-transcription factor II regulates nuclear receptor, myogenic, and metabolic gene expression in skeletal muscle cells

Crowther

Wang

Eriksson

et al. 2011

Physiological Genomics

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Crowther LM, Wang SCM, Eriksson NA, Myers SA, Murray LA, Muscat GEO. Chicken ovalbumin upstream promoter-transcription factor II regulates nuclear receptor, myogenic, and metabolic gene expression in skeletal muscle cells. Physiol Genomics 43: 213-227, 2011. First published November 30, 2010 doi:10.1152/physiolgenomics.00195.2010.-We demonstrate that chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) mRNA is more abundantly expressed (than COUP-TFI mRNA) in skeletal muscle C2C12 cells and in (type I and II) skeletal muscle tissue from C57BL/10 mice. Consequently, we have utilized the ABI TaqMan Low Density Array (TLDA) platform to analyze gene expression changes specifically attributable to ectopic COUP-TFII (relative to vector only) expression in muscle cells. Utilizing a TLDA-based platform and 5 internal controls, we analyze the entire NR superfamily, 96 critical metabolic genes, and 48 important myogenic regulatory genes on the TLDA platform utilizing 5 internal controls. The low density arrays were analyzed by rigorous statistical analysis (with Genorm normalization, Bioconductor R, and the Empirical Bayes statistic) using the (integromics) statminer software. In addition, we validated the differentially expressed pathophysiologically relevant gene (identified on the TLDA platform) glucose transporter type 4 (Glut4). We demonstrated that COUP-TFII expression increased the steady state levels of Glut4 mRNA and protein, while ectopic expression of truncated COUP-TFII lacking helix 12 (COUP-TF⌬H12) reduced Glut4 mRNA expression in C2C12 cells. Moreover, COUP-TFII expression trans-activated the Glut4 promoter (Ϫ997/ϩ3), and ChIP analysis identified selective recruitment of COUP-TFII to a region encompassing a highly conserved SP1 binding site (in mouse, rat, and human) at nt positions Ϫ131/Ϫ118. Mutation of the SpI site ablated COUP-TFII mediated trans-activation of the Glut4 promoter. In conclusion, this study demonstrates that in skeletal muscle cells, COUP-TFII regulates several nuclear hormone receptors, and critical metabolic and muscle specific genes. glucose metabolism; differentiation; TaqMan low density array; myogenesis CHICKEN OVALBUMIN UPSTREAM PROMOTER TRANSCRIPTION FACTORS (COUP-TFs) I and II are orphan members of the nuclear hormone receptor (NR) superfamily. NRs are ligand modulated transcription factors that regulate expression of genes involved in reproduction, development, cell differentiation, and metabolism (22).It is known that COUP-TFI and COUP-TFII can act as transcriptional repressors or activators, and the role of COUPTFs in metabolism has been examined in tissues such as liver and adipose tissue.In liver cells, COUP-TFII stimulates CYP7A (33, 37, 73) and CETP transcription (20), and represses apolipoprotein AI expression (38), demonstrating a role for COUP-TFII in the regulation of cholesterol homeostasis in liver. Also in HepG2 cells, COUP-TFI inhibits transactivation of the CPT-II promoter by PPAR␣/RXR␣, and is required for stimulation of phosphoenolpyruvate ca...

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Modulation of the Androgen Receptor Axis

Mohler

Dalton

2021

Burger's Medicinal Chemistry and Drug Discovery

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The androgen receptor (AR) mediates the endocrine functions of endogenous androgens like testosterone and exerts pleiotropic androgenic (male phenotype development, sexual function) and anabolic (growth and maintenance of musculoskeletal system) effects across most tissues. The AR‐axis, i.e. AR and its downstream effects, is extensively targeted to stimulate anabolism or treat prostatic diseases. Tissue‐selective, direct‐acting synthetic AR agonists are limited in scope by their inadequate separation of anabolic from untoward androgenic or virilizing effects and include FDA approved steroidal androgens (anabolic‐androgenic steroids) and investigational nonsteroidal selective AR modulators (SARMs). Gaining in popularity is testosterone replacement therapy in hypogonadal men. Antagonism of the AR‐axis is common in aging males with androgen‐dependent prostate hyperproliferation [prostate cancer or benign prostatic hyperplasia (BPH)]. Androgen ablation (indirect antagonism) and direct AR antagonism have been the mainstays of prostate cancer therapies for many decades including recent approvals. Indirect antagonists of the AR‐axis include gonadotropin‐releasing hormone agonists or antagonists (androgen‐deprivation therapy), which achieve systemic androgen and estrogen ablation for prostate or breast cancers as a monotherapy or sometimes in combination with steroidogenic enzyme (lyase) inhibitors. DHT‐dependent diseases are treated with 5α‐reductase to block intracrine production of DHT for male pattern baldness and BPH; whereas aromatase inhibitors block androgen metabolism to estrogen in breast cancer. Direct AR antagonists (antiandrogens) with improved potency and anti‐androgenic scope continue to be approved for prostate cancer. Research into innovative ways to directly or indirectly modulate the AR‐axis remains robust, suggesting new therapies will likely be introduced regularly for the foreseeable future.

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Characterisation of the pharmacological profile of desoxymethyltestosterone (Madol), a steroid misused for doping

Cited by 39 publications

References 14 publications

C2C12 myoblastoma cell differentiation and proliferation is stimulated by androgens and associated with a modulation of myostatin and Pax7 expression

C2C12 myoblastoma cell differentiation and proliferation is stimulated by androgens and associated with a modulation of myostatin and Pax7 expression

Chicken ovalbumin upstream promoter-transcription factor II regulates nuclear receptor, myogenic, and metabolic gene expression in skeletal muscle cells

Modulation of the Androgen Receptor Axis

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