Cover: “Modulation of mTOR signaling as a strategy for the treatment of Pompe disease” by Jeong-A Lim, Lishu Li, Orian S. Shirihai, Kyle M. Trudeau, Rosa Puertollano and Nina Raben. The image shows an acid alpha-glucosidase-deficient multinucleated myotube (blue, DAPI-stained nuclei) containing enlarged LAMP1-positive lysosomes (red) decorated with mTORC1 protein (green). The recent discovery of a great deal of interdependence between the lysosomal-autophagic pathway and mTORC1 signaling may pave the way for new therapeutic approaches for lysosomal storage disorders. Here, we report a dysregulation of mTORC1 kinase in Pompe disease, a severe muscle-wasting disorder caused by the lack or deficiency of a glycogen-degrading lysosomal enzyme. We have systematically analyzed the mTOR pathway in Pompe muscle cells by evaluating mTORC1 activity, positioning, response to nutrients, and its role in the control of muscle
protein synthesis and autophagy. We describe a profound mTOR signaling defect in the diseased muscle cells and suggest a model of mTOR dysregulation; we identify the sites of therapeutic intervention and employ lysosomal acidification and manipulation of the TSC2-Rheb pathway to rescue the phenotype. Scientific image by Jeong-A Lim, National Institutes of Health, Bethesda, MD, USA.