Activation of mammalian target of rapamycin induces lipid accumulation in the diaphragm of ventilated rats and hypoxia-treated C2C12 cells

Abstract Background Our previous study demonstrated that ventilators increase diaphragmatic lipid accumulation in rabbits, but their cellular mechanism is poorly understood. Mammalian target of rapamycin (mTOR) plays an important role in atherosclerosis in rat vascular smooth muscle cells. The present study investigated the role of mTOR pathway activation in the diaphragmatic muscle of ventilated rats and hypoxia-induced C2C12 cells. Materials and methods Male Sprague-Dawly rats were randomized into a control group ( n  = 8), controlled mechanical ventilation (CMV) group ( n  = 8), and CMV + Rapa group ( n  = 8). We evaluated the diaphragmatic contractility, lipid accumulation, and protein expression of the mTOR pathways. To explore the mechanism underlying ventilator-induced lipid accumulation, we observed protein expression of the mTOR and low-density lipoprotein receptor (LDLr) pathways in C2C12 cells under hypoxic and mTOR pathway inhibitor treatments. Results Compared with the control group, there was a significant decrease in the peak twitch and peak tetanic forces in the CMV group (384.24 ± 70.39 versus 496.33 ± 78.64 g/cm 2 , P versus 1090.72 ± 118.91 g/cm 2 , P versus 384.24 ± 70.39 g/cm 2 , P versus 869.24 ± 76.67 g/cm 2 , P versus 0.005 ± 0.002, P P versus 0.086 ± 0.009, P P P P Conclusions These data suggest that CMV and hypoxia-induced activation of the mTOR pathway, resulting in lipid accumulation, and impaired the diaphragmatic contractile function. Therefore, pharmacologic agents that inhibit the mTOR pathway could potentially be useful for mitigating the diaphragmatic contractile dysfunction induced by mechanical ventilation.