title: Fenofibrate, a PPAR{alpha} agonist, decreases atrogenes and myostatin expression and improves arthritis-induced skeletal muscle atrophy.
abstract: Arthritis is a chronic inflammatory illness that induces cachexia, which has a direct impact on morbidity and mortality. Fenofibrate, a selective PPARα activator prescribed to treat human dyslipidemia, has been reported to decrease inflammation in rheumatoid arthritis patients. The aim of this study was to elucidate whether fenofibrate is able to ameliorate skeletal muscle wasting in adjuvant-induced arthritis, an experimental model of rheumatoid arthritis. On day 4 after adjuvant injection, control and arthritic rats were treated with 300 mg/kg fenofibrate until day 15, when all rats were euthanized. Fenofibrate decreased external signs of arthritis and liver TNFα and blocked arthritis-induced decreased in PPARα expression in the gastrocnemius muscle. Arthritis decreased gastrocnemius weight, which results from a decrease in cross-section area and myofiber size, whereas fenofibrate administration to arthritic rats attenuated the decrease in both gastrocnemius weight and fast myofiber size. Fenofibrate treatment prevented arthritis-induced increase in atrogin-1 and MuRF1 expression in the gastrocnemius. Neither arthritis nor fenofibrate administration modify Akt-FoxO3 signaling. Myostatin expression was not modified by arthritis, but fenofibrate decreased myostatin expression in the gastrocnemius of arthritic rats. Arthritis increased muscle expression of MyoD, PCNA, and myogenin in the rats treated with vehicle but not in those treated with fenofibrate. The results indicate that, in experimental arthritis, fenofibrate decreases skeletal muscle atrophy through inhibition of the ubiquitin-proteasome system and myostatin.
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid, Spain 28040. ALC@med.ucm.es
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Castillero
authors.forename: María Paz
authors.initials: MP
authors.lastname: Nieto-Bona
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernández-Galaz
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Martín
authors.forename: María
authors.initials: M
authors.lastname: López-Menduiña
authors.forename: Miriam
authors.initials: M
authors.lastname: Granado
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Villanúa
authors.forename: Asunción
authors.initials: A
authors.lastname: López-Calderón
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology*; D001284:Atrophy; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000648:ultrastructure; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology*; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D055435:Myostatin / Q000096:biosynthesis* / Q000235:genetics*; D009929:Organ Size / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017208:Rats, Wistar; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis* / Q000235:genetics; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000960:Hypolipidemic Agents; D008055:Lipids; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D055435:Myostatin; D047495:PPAR gamma; D000070584:Tripartite Motif Proteins; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D011345:Fenofibrate