title: Glucocorticoid antagonist RU38486 fails to block acid-induced muscle wasting in vivo or in vitro.
abstract: BACKGROUND
  Increased protein degradation during metabolic acidosis contributes to muscle wasting in uraemia. Adrenalectomy experiments in severely acidotic rats (arterial pH approximately 7.15) have shown that this is prevented in the absence of glucocorticoid. It should therefore be possible to block such muscle wasting with glucocorticoid receptor antagonist 11beta-(4-dimethylaminophenyl)-17beta-hydroxy,-17a-(prop-1-ynyl)-estra-4,9-dien-3-one (RU38486).
  
  
  METHODS
  The effect of oral RU38486 (50 mg/kg body weight/day) was studied in vivo by administration to rats receiving dietary HCl supplements which yielded moderate acidosis (plasma HCO(3)(-) 19.7 +/- 1.2 mmol/l), comparable with that observed in uraemia. The effect of the glucocorticoid dexamethasone (DEX) (up to 500 nmol/l) and RU38486 (up to 5 micro mol/l) was also studied in vitro in acidified cultures of L6-G8C5 rat skeletal muscle cells.
  
  
  RESULTS
  In vivo 15 days of moderate acidosis slowed weight gain and induced muscle wasting (6% weight loss in gastrocnemius with a commensurate decline in muscle protein) but, at this level of acidosis, muscle protein degradation showed no detectable increase. Wasting was not inhibited by RU38486 in spite of blockade of 80% of the glucocorticoid receptors in gastrocnemius. Unexpectedly, weight gain was significantly slower in acidotic rats receiving RU38486 than in acidotic rats receiving vehicle. In vitro acid spontaneously stimulated protein degradation, but even under strongly acidic conditions (pH 7.1) this was only weakly and transiently stimulated by 5 nmol/l DEX and transiently blunted by 5 micro mol/l RU38486. In contrast, as little as 1 nmol/l insulin-like growth factor I (IGF-I) almost abolished the effect of acid and this was partly restored by 5 nmol/l DEX.
  
  
  CONCLUSIONS
  IGF-I is a potent determinant of acid-induced protein degradation in vitro and is antagonized by glucocorticoid. If glucocorticoid acts in this indirect way in vivo this may explain why, in moderate metabolic acidosis with intact adrenal glands, the action of RU38486 via glucocorticoid is too weak to be of therapeutic value.
authors.affiliation: Department of Nephrology, Leicester General Hospital, Leicester, UK.
authors.forename: Warren P
authors.initials: WP
authors.lastname: Pickering
authors.forename: Frease E
authors.initials: FE
authors.lastname: Baker
authors.forename: Jeremy
authors.initials: J
authors.lastname: Brown
authors.forename: Heather L
authors.initials: HL
authors.lastname: Butler
authors.forename: Sheena
authors.initials: S
authors.lastname: Govindji
authors.forename: Julie M
authors.initials: JM
authors.lastname: Parsons
authors.forename: Izabella Z A
authors.initials: IZ
authors.lastname: Pawluczyk
authors.forename: John
authors.initials: J
authors.lastname: Walls
authors.forename: Alan
authors.initials: A
authors.lastname: Bevington
mesh_terms: D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006727:Hormone Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*
chemical_list: D006727:Hormone Antagonists; D036341:Intercellular Signaling Peptides and Proteins; D011965:Receptors, Glucocorticoid; C065700:myotrophin; D015735:Mifepristone; D007334:Insulin-Like Growth Factor I