Extracellular Signal–Regulated Kinase–Mammalian Target of Rapamycin Signaling and Forkhead-Box Transcription Factor 3a Phosphorylation Are Involved in Testosterone’s Effect on Severe Burn Injury in a Rat Model

ABSTRACTBackgroundTestosterone and androgen receptor agonists have been known for a long time to prevent or reverse muscle wasting in burn injury patients, but the exact molecular mechanisms are not clear. ObjectiveTo investigate the underlying molecular mechanisms of testosterone in severely burned rats. MethodsSevere burn injuries were induced by immersing the back of the rat in 100°C water for 12 s. Rats were treated for 14 days with vehicle (burn group) or a physiological replacement dose of testosterone (B + T group) immediately after injury. Gene and protein expressions were assessed by real-time polymerase chain reaction and Western blot. ResultsTestosterone improved glucose metabolism, reduced body weight loss, and attenuated tibialis anterior muscle mass loss and muscle protein breakdown. In rat tibialis anterior muscle, testosterone positively regulated the insulin-sensitive glucose transporters Glut3 and Glut4 genes and glycogen synthase 1 protein. These changes would be expected to improve glucose metabolism and nutrient availability in skeletal muscle. Administration of testosterone negatively regulated atrogin 1 (Fbxo32) by increasing total and phosphorylated Foxo3a (forkhead-box transcription factor 3a) levels and positively regulated the expression of the mammalian target of rapamycin (mTOR) and its downstream proteins p70S6 and S6 through mTOR–extracellular signal–regulated kinase phosphorylation. ConclusionsResults suggested that testosterone might regulate skeletal muscle glucose and protein metabolism following burn injury in part by affecting extracellular signal–regulated kinase–mTOR signaling and Foxo3a levels.