Characterization of GLPG0492, a selective androgen receptor modulator, in a mouse model of hindlimb immobilization

BMC Musculoskeletal Disorders

Florence Namour¹  Philippe Delerive¹  Philippe Clément-Lacroix¹  Céline Cottereaux¹  Didier Merciris¹  Dominique Minet¹  Marielle Auberval¹  Liên Lepescheux¹  Roland Blanqué¹ 

[1] GALAPAGOS SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France

关键词: Anabolism;    Muscle wasting;    Immobilization;    Selective androgen receptor modulator;   

Others  :  1125420
DOI  :  10.1186/1471-2474-15-291

 received in 2014-02-26, accepted in 2014-08-27,  发布年份 2014

【 摘 要 】

Background

Muscle wasting is a hallmark of many chronic conditions but also of aging and results in a progressive functional decline leading ultimately to disability. Androgens, such as testosterone were proposed as therapy to counteract muscle atrophy. However, this treatment is associated with potential cardiovascular and prostate cancer risks and therefore not acceptable for long-term treatment. Selective Androgen receptor modulators (SARM) are androgen receptor ligands that induce muscle anabolism while having reduced effects in reproductive tissues. Therefore, they represent an alternative to testosterone therapy. Our objective was to demonstrate the activity of SARM molecule (GLPG0492) on a immobilization muscle atrophy mouse model as compared to testosterone propionate (TP) and to identify putative biomarkers in the plasma compartment that might be related to muscle function and potentially translated into the clinical space.

Methods

GLPG0492, a non-steroidal SARM, was evaluated and compared to TP in a mouse model of hindlimb immobilization.

Results

GLPG0492 treatment partially prevents immobilization-induced muscle atrophy with a trend to promote muscle fiber hypertrophy in a dose-dependent manner. Interestingly, GLPG0492 was found as efficacious as TP at reducing muscle loss while sparing reproductive tissues. Furthermore, gene expression studies performed on tibialis samples revealed that both GLPG0492 and TP were slowing down muscle loss by negatively interfering with major signaling pathways controlling muscle mass homeostasis. Finally, metabolomic profiling experiments using ¹H-NMR led to the identification of a plasma GLPG0492 signature linked to the modulation of cellular bioenergetic processes.

Conclusions

Taken together, these results unveil the potential of GLPG0492, a non-steroidal SARM, as treatment for, at least, musculo-skeletal atrophy consecutive to coma, paralysis, or limb immobilization.

【 授权许可】

   
2014 Blanqué et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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