title: Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle.
abstract: Chronic arthritis is a catabolic state associated with an inhibition of the IGF system and a decrease in body weight. Cachexia and muscular wasting is secondary to protein degradation by the ubiquitin-proteasome pathway. The aim of this work was to analyze the effect of adjuvant-induced arthritis on the muscle-specific ubiquitin ligases muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) as well as on IGF-I and IGF-binding protein-5 (IGFBP-5) gene expression in the skeletal muscle. We also studied whether the synthetic ghrelin receptor agonist, growth hormone releasing peptide-2 (GHRP-2), was able to prevent arthritis-induced changes in the skeletal muscle. Arthritis induced an increase in MuRF1, MAFbx (P < 0.01), and tumor necrosis factor (TNF)-alpha mRNA (P < 0.05) in the skeletal muscle. Arthritis decreased the serum IGF-I and its gene expression in the liver (P < 0.01), whereas it increased IGF-I and IGFBP-5 gene expression in the skeletal muscle (P < 0.01). Administration of GHRP-2 for 8 days prevented the arthritis-induced increase in muscular MuRF1, MAFbx, and TNF-alpha gene expression. GHRP-2 treatment increased the serum concentrations of IGF-I and the IGF-I mRNA in the liver and in the cardiac muscle and decreased muscular IGFBP-5 mRNA both in control and in arthritic rats (P < 0.05). GHRP-2 treatment increased muscular IGF-I mRNA in control rats (P < 0.01), but it did not modify the muscular IGF-I gene expression in arthritic rats. These data indicate that arthritis induces an increase in the activity of the ubiquitin-proteasome proteolytic pathway that is prevented by GHRP-2 administration. The parallel changes in muscular IGFBP-5 and TNF-alpha gene expression with the ubiquitin ligases suggest that they can participate in skeletal muscle alterations during chronic arthritis.
authors: Dept Fisiología, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.
authors: Miriam
authors: M
authors: Granado
authors: Teresa
authors: T
authors: Priego
authors: Ana I
authors: AI
authors: Martín
authors: Maria Angeles
authors: MA
authors: Villanúa
authors: Asunción
authors: A
authors: López-Calderón
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology*; D015870:Gene Expression / Q000187:drug effects; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008099:Liver / Q000737:chemistry; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000201:enzymology*; D009842:Oligopeptides / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D054440:Receptors, Ghrelin; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D018975:Insulin-Like Growth Factor Binding Protein 5; D009124:Muscle Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D000070584:Tripartite Motif Proteins; D007334:Insulin-Like Growth Factor I; C091874:growth hormone-releasing peptide-2; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases