title: Characterization of GLPG0492, a selective androgen receptor modulator, in a mouse model of hindlimb immobilization.
abstract: 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.
authors.forename: Roland
authors.initials: R
authors.lastname: Blanqué
authors.forename: Liên
authors.initials: L
authors.lastname: Lepescheux
authors.forename: Marielle
authors.initials: M
authors.lastname: Auberval
authors.forename: Dominique
authors.initials: D
authors.lastname: Minet
authors.forename: Didier
authors.initials: D
authors.lastname: Merciris
authors.forename: Céline
authors.initials: C
authors.lastname: Cottereaux
authors.affiliation: GALAPAGOS SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France. philippe.clement-lacroixl@glpg.com.
authors.forename: Philippe
authors.initials: P
authors.lastname: Clément-Lacroix
authors.forename: Philippe
authors.initials: P
authors.lastname: Delerive
authors.forename: Florence
authors.initials: F
authors.lastname: Namour
mesh_terms: D000728:Androgens / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D019417:Hindlimb Suspension / Q000379:methods / Q000502:physiology*; D006827:Hydantoins / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009133:Muscular Atrophy / Q000188:drug therapy / Q000503:physiopathology; D011944:Receptors, Androgen / Q000502:physiology*
chemical_list: C577110:4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; D000728:Androgens; D006827:Hydantoins; D011944:Receptors, Androgen