Skeletal Muscle Resistance To Leucine Induced Signal Transduction And Regulation Of Autophagy In Acute Kidney Injury (Aki)
FASEB JOURNAL(2012)
摘要
Protection against muscle wasting with leucine(LEU) is of particular interest in AKI patients as it can cause activation of the mTOR pathway and reduce autophagy(ATG), elevated in AKI. Since LEU resistance develops in other acute catabolic conditions we investigated if LEU is effective in stimulating skeletal muscle mTOR signaling and inhibiting ATG, in AKI. Rats with AKI and sham operated controls(CON) were gavaged with LEU or saline(Sal) and sacrificed 60 mins later. Results show that basal Akt, mTOR, 4eBP1, S6k1, FOXO3a and LC3B‐II protein plus IL‐ 6 mRNA were all elevated in AKI. Compared to Sal, LEU significantly stimulated mTOR, 4eBP1, S6K1 and rpS6 in CON but only rpS6 in AKI. Akt activation was lower after LEU in both groups and LEU suppressed LC3B‐II protein levels in CON. LEU also lowered AMPK in CON, but not AKI. The failure of LEU to stimulate the mTOR pathway and failure to suppress both AMPK and ATG strikingly demonstrates that severe AKI induces a leucine resistant state. We suggest that this nutrient resistant state contributes to protein energy wasting that often persists in critically ill AKI patients despite nutritional supplementation. Funded by VA Merit Award and CDA‐1.
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关键词
autophagy,acute kidney injury,leucine induced signal transduction,skeletal muscle resistance,skeletal muscle
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