Role Of MTOR Kinase Activity In Skeletal Muscle Integrity And Physiology

Mammalian target of rapamycin(mTOR)is a key protein kinase that integrates and coordinates diverse signaling information mediated by growth factors,nutrient availability and energy status.It forms at least two functionally distinct signaling complexes,named mTOR Complex 1(mTORC1)and mTOR Complex 2(mTORC2).mTOR regulates a great deal of cellular activities such as translation,transcription,autophagy,etc.The knockout of mTOR in mice is embryonic lethal.Mice with skeletal muscle-specific deletion of mTOR suffer from a progressive myopathy that causes premature death,and exhibited muscle atrophy,impaired mitochondrial function and increased glycogen content.My study aims to characterize the role of mTOR kinase activity in muscle integrity and function.To this aim,I have generated a mouse line named mTOR MKOKI which is defective in endogenous muscle mTOR(mTOR MKO),while expressing a FLAG-tagged muscle-specific kinase-inactive allele(Asp2357Glu)of mTOR(FLAGmTOR MKI),thereby mimicking the effects of a potent,bioavailable and selective mTOR catalytic inhibitor in muscle.Here I describe the phenotype of MKOKI and compared it with MKO phenotype.I found that:1)a mTOR kinase dead allele did not rescue any altered parameters associated to the loss of the mTOR protein,but in contrast exacerbates these alterations.2)Muscle mTOR kinase activity was required for oxidative metabolism maintenance and dystrophin expression.3)MKOKI muscles show a hyper-accumulation of glycogen that gave rise to myofibrillar disorganization,a feature not observed in MKO.4)Glycogen hyper-accumulation is due to a stronger Akt hyperactivation that leads to myophosphorylase downregulation.Glycogen degradation inhibition gave rise to myofibrillar disorganization following glycogenosis.Sustained muscle Aktl and Akt2 activation actually improved glucose uptake and storage as glycogen but also compromised its utilization further leading to severe Glycogen StorageDisease.5)Autophagy inhibition in mTOR MKOKI,in contrast to MKO further leaded to pronounced atrophy,dystrophy.6)mTOR catalytic inhibitors might have severe mutiple effects in postmitotic tissues such as skeletal muscles,which are able to activate the feedback loop on Akt due to mTOR kinase inhibition.