No abstract

A. Fenofibrate, a PPAR␣ agonist, decreases atrogenes and myostatin expression and improves arthritis-induced skeletal muscle atrophy. Am J Physiol Endocrinol Metab 300: E790 -E799, 2011. First published February 8, 2011 doi:10.1152/ajpendo.00590.2010.-Arthritis is a chronic inflammatory illness that induces cachexia, which has a direct impact on morbidity and mortality. Fenofibrate, a selective PPAR␣ 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 TNF␣ and blocked arthritis-induced decreased in PPAR␣ 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.

Castillero E, Martín AI, López-Menduiña M, Villanúa MA, López-Calderón A. Eicosapentaenoic acid attenuates arthritis-induced muscle wasting acting on atrogin-1 and on myogenic regulatory factors. Am J Physiol Regul Integr Comp Physiol 297: R1322-R1331, 2009. First published September 9, 2009 doi:10.1152/ajpregu.00388.2009.-Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid that has anti-inflammatory and anticachectic actions. The aim of this work was to elucidate whether EPA administration is able to prevent an arthritis-induced decrease in body weight and muscle wasting in rats. Arthritis was induced by intradermal injection of Freund's adjuvant; 3 days later, nine rats received 1 g/kg EPA or coconut oil daily. All rats were killed 15 days after adjuvant injection. EPA administration decreased the external signs of arthritis and paw volume as well as liver TNF-␣ mRNA. EPA did not modify arthritis-induced decrease in food intake or body weight gain. However, EPA treatment prevented arthritis-induced increase in muscle TNF-␣ and atrogin-1, whereas it attenuated the decrease in gastrocnemius weight and the increase in MuRF1 mRNA. Arthritis not only decreased myogenic regulatory factors but also increased PCNA, MyoD, and myogenin mRNA in the gastrocnemius. Western blot analysis showed that changes in protein content followed the pattern seen with mRNA. In the control rats, EPA administration increased PCNA and MyoD mRNA and protein.In arthritic rats, EPA did not modify the stimulatory effect of arthritis on these myogenic regulatory factors. The results suggest that in experimental arthritis, in addition to its anti-inflammatory effect, EPA treatment attenuates muscle wasting by decreasing atrogin-1 and MuRF1 gene expression and increasing the transcription factors that regulate myogenesis. adjuvant-induced arthritis; ubiquitin-proteasome system; MyoD; myogenin; proliferating cell nuclear antigen CHRONIC INFLAMMATORY DISEASES such as cancer, sepsis, and rheumatoid arthritis are associated with a decrease in body weight, skeletal muscle atrophy, and cachexia. Cachexia is a complex metabolic syndrome associated with underlying

Adjuvant-induced arthritis is a model of rheumatoid arthritis that induces cachexia. In other cachectic situations, there is an increase in lipolysis resulting in a loss of adipose tissue mass. The aim of this work was to analyse the effect of chronic arthritis, induced by adjuvant injection, on white adipose tissue (WAT). For this purpose, rats were killed 10 days after adjuvant injection, when the first external symptoms appeared, on days 15 and 22 when the external signs of the illness reach their severest level. As arthritis decreases food intake, a pair-fed group was also included. Serum concentrations of insulin, leptin, adiponectin, glycerol and nitrites, as well as gene expression of leptin, adiponectin, hormonesensitive lipase (HSL), fatty acid synthase (FAS), tumour necrosis factor a and zinc-a 2 -glycoprotein (ZAG) were determined. Arthritis decreased food intake between days 5 and 16, but not during the last 5 days of the experiment. There was a marked decrease in relative adipose tissue weight and in serum leptin and adiponectin as well as in their gene expression in WAT in arthritic rats. Arthritis decreased the gene expression of FAS in the WAT. However, none of these effects was found in pair-fed rats. Arthritis did not increase lipolysis, since arthritic rats have lower serum concentrations of glycerol, HSL mRNA in WAT, as well as liver ZAG mRNA than the pair-fed or control rats. These data suggest that in chronic arthritis the decrease in white adipose mass is secondary to a reduced adipose lipogenesis, and this effect is not mainly due to the decrease in food intake.

Adjuvant arthritis is an animal model of rheumatoid arthritis that decreases liver and circulating IGF-I as well as skeletal muscle mass. The aim of this work was to elucidate whether IGF-I administration was able to prevent the effect of arthritis on body weight and on two skeletal muscles, gastrocnemius and soleus. On day 4 after adjuvant injection, control and arthritic rats were treated with IGF-I (100 microg/kg s.c.) two times a day, until day 15 when all rats were killed. Arthritis decreased body weight gain and gastrocnemius weight. In arthritic rats, IGF-I treatment increased body weight gain and gastrocnemius weight, without modifying food intake or the external signs of arthritis. Arthritis increased atrogin-1 and muscle ring finger 1 (MuRF1) gene expression in the gastrocnemius and to a lesser extent in the soleus muscle. IGF-I attenuated the arthritis-induced increase in atrogin-1 and MuRF1 expression in the gastrocnemius, whereas it did not modify the expression of these genes in the soleus muscle. Arthritis also increased IGF-binding protein (IGBP)-3 and IGFBP-5 gene expression in gastrocnemius and soleus, whereas IGF-I administration decreased IGFBP-3, but not IGFBP-5, gene expression in both muscles. In both groups of arthritic rats and in control rats treated with IGF-I, proliferating cell nuclear antigen and myogenic differentiation proteins were increased in the gastrocnemius. These data suggest that the inhibitory effect of chronic arthritis on skeletal muscle is higher in fast glycolytic than in slow oxidative muscle and that IGF-I administration attenuates this effect and decreases atrogin-1 and IGFBP-3 gene expression.