Regulation of myostatin by glucocorticoids after thermal injury.

Myostatin is a negative regulator of muscle mass that may contribute to the muscle wasting observed in response to traumatic injury. The purpose of this study was to determine whether muscle myostatin mRNA abundance was altered by different traumatic insults and whether the change in myostatin was associated with alterations in insulin-like growth factor (IGF)-I and IGF-II mRNA in gastrocnemius, or the concentration of glucocorticoids in plasma. The abundance of myostatin mRNA was increased threeto fourfold in gastrocnemius 24 h after a 30% total body surface area burn injury. In contrast, neither the injection of endotoxin nor the induction of peritonitis significantly altered myostatin mRNA at the same time point. IGF-I mRNA in muscle was decreased (40–60%) by all insults, whereas the abundance of IGF-II mRNA was unaltered. The plasma concentration of corticosterone was increased approximately threefold after burn injury, was only transiently elevated after endotoxin, and was only mildly increased (25%) in septic rats at the time of sacrifice. Pretreatment with the type II glucocorticoid receptor antagonist RU486 prevented the increased myostatin mRNA and decreased muscle protein content after burn. A single injection of dexamethasone in naive control animals increased muscle myostatin mRNA by 60% and 2.7-fold at 4 h and 24 h, respectively. In contrast, pretreatment of burn rats with tumor necrosis factor binding protein (TNFBP), which antagonizes the actions of this cytokine, failed to prevent the burn-induced increase in myostatin mRNA or the loss of muscle protein. The results of this study indicate that thermal injury, but not endotoxin or sepsis, increases myostatin mRNA content. Moreover, the burn-induced increase in myostatin appears to be largely mediated by the enhanced endogenous secretion of glucocorticoids and independent of changes in IGF-I, IGF-II, or TNF.