Proceedings of The Physiological Society
University of Manchester (2010) Proc Physiol Soc 19, C137
PPAR?? agonist fenofibrate blocks arthritis induced soleus muscle atrophy by inhibiting proteolysis and stimulating regeneratory response
E. Castillero1, M. López-Menduiña1, A. Martín1, M. Villanúa1, A. López-Calderón1
1. Physiology, Complutense University of Madrid, Madrid, Spain.
Adjuvant-induced arthritis is an animal model of cachexia characterized by skeletal muscle atrophy and body weight loss. Muscle wasting is associated with the upregulation of proteolysis by ubiquitin-protheasome pathway. It has been reported that peroxisomal proliferator-activated receptor alpha (PPARα) plays a major role regulating inflammatory processes. Aim: To evaluate whether PPARα agonist fenofibrate is able to prevent the symptoms of arthritis and its effects on the oxidative slow twitch soleus muscle. Methods: Arthritis was induced in male Wistar rats by an intradermal injection of Freund’s adjuvant. Three days after the injection control and arthritis rats were divided in two experimental groups. One group was daily gavaged with 300mg/kg bw of fenofibrate and the other was gavaged with vehicle. After 12 days of treatment rats were killed by decapitation, and soleus muscles were weighted and dissected. Gene expression of ubiquitin ligases MAFbx and Murf-1 in the soleus were measured by real-time PCR. Protein levels of Miogenin, MyoD and PCNA were measured by Western blot. Results: Fenofibrate administration ameliorated arthritis score and hindpaw swelling in arthritic rats (P<0.01). Arthritis decreased body weight gain and fenofibrate reduced body weigh loss (P<0.01). Arthritis decreased the weight of soleus muscle (P<0.01), whereas fenofibrate completely reverted this effect (P<0.01). Fenofibrate prevented arthritis-induced increase in atrogenes MAFbx and Murf-1 mRNA in soleus muscle (P<0.01). Protein levels of the regeneratoy factors MyoD and Miogenin and proliferatory factor PCNA were increased by arthritis (P<0.01). Fenofibrate treatment increased the levels of these proteins to higher levels than those of the arthritic rats (P<0.05) Conclusion: Fenofibrate prevents arthritis-induced atrophy of the soleus muscle by inhibiting ubiquitin-protheasome pathway and increasing regeneratoty and proliferatory factors.
Where applicable, experiments conform with Society ethical requirements