No abstract

Glucocorticoid-induced muscle atrophy is characterized by fast-twitch or type II muscle fiber atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. Muscle proteolysis, in particular through the ubiquitin-proteasome system (UPS), is considered to play a major role in the catabolic action of glucocorticoids. The stimulation by glucocorticoids of the UPS is mediated through the increased expression of several atrogenes ('genes involved in atrophy'), such as atrogin-1 and MuRF-1, two ubiquitin ligases involved in the targeting of protein to be degraded by the proteasome machinery. Glucocorticoids also exert an anti-anabolic action by blunting muscle protein synthesis. These changes in protein turnover may result from changes in the production of two growth factors which control muscle mass, namely IGF-I and myostatin respectively anabolic and catabolic toward the skeletal muscle. The decreased production of IGF-I as well as the increased production of myostatin have been both demonstrated to contribute to the muscle atrophy caused by glucocorticoids. At the molecular level, IGF-I antagonizes the catabolic action of glucocorticoids by inhibiting, through the PI3-kinase/Akt pathway, the activity of the transcription factor FOXO, a major switch for the stimulation of several atrogenes. These recent progress in the understanding of the glucocorticoidinduced muscle atrophy should allow to define new therapies aiming to minimize this myopathy. Promising new therapeutic approaches for treating glucocorticoid-induced muscle atrophy are also presented in this review.

Glucocorticoids mediate muscle atrophy in many catabolic states. Myostatin expression, a negative regulator of muscle growth, is increased by glucocorticoids and myostatin overexpression is associated with lower muscle mass. This suggests that myostatin is required for the catabolic effects of glucocorticoids. We therefore investigated whether myostatin gene disruption could prevent muscle atrophy caused by glucocorticoids. Male myostatin knockout (KO) and wild-type mice were subjected to dexamethasone treatment (1 mg/kg.d for 10 d or 5 mg/kg.d for 4 d). In wild-type mice, daily administration of low-dose dexamethasone for 10 d resulted in muscle atrophy (tibialis anterior: -15%; gastrocnemius: -13%; P < 0.01) due to 15% decrease in the muscle fiber cross-sectional area (1621 +/- 31 vs. 1918 +/- 64 microm(2), P < 0.01). In KO mice, there was no reduction of muscle mass nor fiber cross-sectional area after dexamethasone treatment. Muscle atrophy after 4 d of high-dose dexamethasone was associated with increased mRNA of enzymes involved in proteolytic pathways (atrogin-1, muscle ring finger 1, and cathepsin L) and increased chymotrypsin-like proteasomal activity. In contrast, the mRNA of these enzymes and the proteasomal activity were not significantly affected by dexamethasone in KO mice. Muscle IGF-I mRNA was paradoxically decreased in KO mice (-35%, P < 0.05); this was associated with a potentially compensatory increase of IGF-II expression in both saline and dexamethasone-treated KO mice (2-fold, P < 0.01). In conclusion, our results show that myostatin deletion prevents muscle atrophy in glucocorticoid-treated mice, by blunting the glucocorticoid-induced enhanced proteolysis, and suggest an important role of myostatin in muscle atrophy caused by glucocorticoids.

MafBx and Murf are two new rat E3 ubiquitin ligases induced in muscle atrophy. Our goal was to investigate whether lipopolysaccharide (LPS) injection, a model of muscle catabolism, is associated with increased expression of MafBx and Murf. LPS (750 W Wg/100 g body weight) induces MafBx and Murf mRNA (respectively, 23-fold and 33-fold after 12 h; P 6 0.001). A transient induction of tumor necrosis factor-K K mRNA (21-fold; P 6 0.001 at 3 h) and a decrease of insulin like growth factor-I mRNA (50%; P 6 0.001 at 6 h), two potential regulators of the ubiquitin^proteasome system were also demonstrated. In summary, MafBx and Murf mRNA are upregulated in response to LPS and might play a role in the muscle proteolysis observed. ß

In catabolic conditions, atrogin-1/MAFbx, a muscle-specific ubiquitin-ligase required for muscle atrophy, is increased, and concentrations of IGF-I, a growth factor known to have antiproteolytic action, are reduced. To define the relationship between the decline in IGF-I and the induction of atrogin-1/MAFbx, we studied the effect of IGF-I replacement on atrogin-1/MAFbx mRNA in rats fasted for 51 h and in rats made diabetic with streptozotocin (STZ). Fasting produced a 5.8-fold increase in atrogin-1/MAFbx (P < 0.001). This was attenuated to a 2.5-fold increase by injections of IGF-I (P < 0.05 vs. fasting). Animals with STZ-induced diabetes experienced a 15.1-fold increase in atrogin-1/MAFbx (P < 0.001). Normalization of their circulating IGF-I concentrations by IGF-I infusion blunted the induction of atrogin-1/MAFbx to 6.3-fold (P < 0.05 vs. STZ diabetes without IGF-I). To further delineate the regulation of atrogin-1/MAFbx by IGF-I, we studied a model of cultured muscle cells. We observed that IGF-I produced a time- and dose-dependent reduction of atrogin-1/MAFbx mRNA, with a 50% effective dose of 5 nm IGF-I, a physiological concentration. The degradation rate of atrogin-1/MAFbx mRNA was not affected by IGF-I, suggesting that the reduction of atrogin-1/MAFbx mRNA by IGF-I is a transcriptional effect. Exposure of muscle cells in culture to dexamethasone increased atrogin-1/MAFbx mRNA with a 50% effective dose of 10 nm, a pharmacological concentration. In the presence of dexamethasone, IGF-I at physiological concentrations retained its full inhibitory effect on atrogin-1/MAFbx mRNA. We conclude that IGF-I inhibits atrogin-1/MAFbx expression and speculate that this effect might contribute to the antiproteolytic action of IGF-I in muscle.