Systemic IGF-I administration attenuates the inhibitory effect of chronic arthritis on gastrocnemius mass and decreases atrogin-1 and IGFBP-3

Abstract

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.

The melanocortin receptor type 3 agonistd-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic rats

“…Our data show that fast fibre was affected more than slow fibre in arthritic rats and are in accordance with the fact that in cachexia induced by inflammatory illness, fast glycolytic muscles are more prone to atrophy than slow oxidative muscles 8, 39…”

“…Inflammatory response includes an increased release of cytokines, such as tumor necrosis factor (TNF‐α), and of glucocorticoids, which are well known inducers of muscle wasting 6, 7. In addition, inflammation decreases insulin‐like growth factor I (IGF‐I) serum levels,8, 9 which is an anabolic hormone that increases muscle mass by stimulating protein synthesis and preventing muscle proteolysis 8, 10. Therefore, the increased release of cytokines and glucocorticoids along with the decreased secretion of IGF‐I might play an important role in inflammatory cachexia.…”

Fenofibrate, a PPARα agonist, decreases atrogenes and myostatin expression and improves arthritis-induced skeletal muscle atrophy

“…However, the atrophy is higher in fast-twitch fibers. These data are in accord with the fact that in arthritic rats muscle atrophy is higher in gastrocnemius, a mixed muscle consisting mainly of fast-twitch fibers, than in soleus, a slow-twitch muscle (31). They also suggest that slow-twitch muscle is more resistant to arthritis-induced atrophy than fast fibers.…”

Comparison of the effects of the n-3 polyunsaturated fatty acid eicosapentaenoic and fenofibrate on the inhibitory effect of arthritis on IGF1

“…Similarly, GH administration to juvenile RA patients increases growth (Touati et al 1998). Furthermore, exogenous IGF1 administration to arthritic rats increases body and skeletal muscle weights (López-Menduiña et al 2010). All these data indicate that arthritis-induced decrease in circulating IGF1 is an important contributor to the decrease in body weight and skeletal muscle wasting induced by experimental arthritis.…”

“…In addition to its anti-inflammatory effect, EPA ameliorates arthritis-induced skeletal muscle wasting by decreasing atrogin-1 and Murf-1 gene expression and also increasing the transcription factors that regulate myogenesis (Castillero et al 2009a). Taking into account that the beneficial effect of IGF1 treatment on skeletal muscle in arthritic rats is also associated with decreased atrogin-1 and increased myogenic regulatory factors (López-Menduiña et al 2010), it is possible that EPA administration can prevent arthritis-induced inhibition of IGF1.…”