Defective Autophagy in GNE Myopathy is Reversed by Inhibition of Supplementary mTOR Activation [cells RNA-seq]

Similar to other autophagic vacuolar myopathies, defective autophagy has been identified as a causative factor in GNE myopathy. However, the molecular mechanism underlying this defective autophagy has not been fully determined.

Through transcriptome analysis of two GNE myoblast models derived from human pluripotent stem cells (hPSCs), several gene sets associated with autophagy were identified as pathogenic gene signatures of GNE myopathy. This prediction, along with subsequent biochemical validation using GNE knockout in C2C12 myoblasts (KO cells), revealed that high production of extracellular matrix promoted focal adhesion and subsequent activation of the AKT-mTORC axis, leading to inhibitory phosphorylation of ULK1 and impeding autophagy initiation in KO cells.