title: The melanocortin receptor type 3 agonist d-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic rats.
abstract: BACKGROUND
  Chronic inflammatory diseases induce cachexia that increases mortality and morbidity of the illness. Adjuvant-induced arthritis is an experimental model of rheumatoid arthritis that is associated with body weight loss and muscle wasting. Alpha-melanocyte stimulating hormone has an anti-inflammatory effect in arthritic rats and decreases muscle wasting. The aim of this work was to elucidate whether the anti-cachectic action of alpha-melanocyte stimulating hormone is mediated by the melanocortin receptor type 3 pathway.
  
  
  METHODS
  Arthritis was induced in male Wistar rats by intradermal injection of Freund's adjuvant, and 6 days afterwards, arthritic rats were injected with the selective melanocortin receptor type 3 agonist d-Trp(8)-gammaMSH ( d-Trp(8)-γMSH) 500 µg/kg subcutaneously. or saline twice a day, for 10 days.
  
  
  RESULTS
  d-Trp(8)-γMSH decreased the external signs of inflammation and body weight loss, but it was not able to modify the anorexigenic effect of arthritis or the increase in hypothalamic cyclooxygenase-2 (COX-2) expression. In contrast, d-Trp(8)-γMSH prevented arthritis-induced increase in hypothalamic IL-1β and serum corticosterone levels and the decrease in serum IGF-I levels. d-Trp(8)-γMSH treatment also prevented arthritis-induced NF-kB(p65) phosphorylation and tumour necrosis factor-α mRNA increase in the gastrocnemius. d-Trp(8)-γMSH administration to arthritic rats increased gastrocnemius mass, its cross-sectional area, and mean fast fibre area. Those effects of d-Trp(8)-γMSH were associated with a decreased expression of atrogin-1 and muscle ring-finger protein-1 in the gastrocnemius. In rats treated with saline, arthritis increased the expression of autophagy marker genes LC3b, Bnip-3, and Gabarap1 as well as the conversion of LC3b I to LC3b II by lipidation in the gastrocnemius. d-Trp(8)-γMSH decreased gastrocnemius LC3b, Bnip-3, and Gabarap1 mRNA expression and prevented the increase in LC3b II in arthritic rats.
  
  
  CONCLUSIONS
  These data suggest that d-Trp(8)-γMSH administration prevents the effect of arthritis on corticosterone and insulin-like growth factor-I serum levels and decreases muscle wasting, by down-regulating atrogenes and autophagy through modifying the NF-kB(p65)/tumour necrosis factor-α signalling transduction pathway.
authors.affiliation: Department of Physiology, Faculty of Medicine Complutense University Madrid Spain.
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Gómez-SanMiguel
authors.affiliation: Department of Physiology, Faculty of Medicine Complutense University Madrid Spain.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Martín
authors.affiliation: Department of Basic Sciences in Health, Faculty of Health Sciences Rey Juan Carlos University Madrid Spain.
authors.forename: María Paz
authors.initials: MP
authors.lastname: Nieto-Bona
authors.affiliation: Department of Physiology, Faculty of Medicine Complutense University Madrid Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernández-Galaz
authors.affiliation: Department of Physiology, Faculty of Medicine Complutense University Madrid Spain.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Villanúa
authors.affiliation: Department of Physiology, Faculty of Medicine Complutense University Madrid Spain.
authors.forename: Asunción
authors.initials: A
authors.lastname: López-Calderón
keywords: Atrogenes; Autophagy; Corticosterone; IGF‐I; Muscle wasting; NF‐kB; γMSH