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.

Background: Testosterone 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.

Objective: To investigate the underlying molecular mechanisms of testosterone in severely burned rats.

Methods: Severe 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.

Results: Testosterone 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.

Conclusions: RESULTS 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.