| The mammalian Target of Rapamycin Complex 1 (mTORC1) increases protein synthesis and inhibits macroautophagy and thereby protein degradation. In Pompe disease, a functional deficiency in lysosomal acid-α-glucosidase results in accumulation of its substrate, glycogen. The primary and most consequential symptom of the disease is muscle weakness and wasting. Single muscle fibers isolated from Pompe disease mouse models exhibit swollen lysosomes whose pH is elevated. Considering that the final regulatory steps of mTORC1 activation occur on the surface of the lysosomal membrane, we checked if these morphologic and biochemical anomalies affected mTORC1 activation. We found that acutely decreasing lysosomal acidity is sufficient to reduce mTORC1 activation in C2C12 myoblasts and myotubes. In addition, mTORC1 activation is reduced in glucosidase-knockdown C2C12 myoblasts and human skin fibroblasts of Pompe disease patients. Reduced mTORC1 activation in glucosidase-knockdown C2C12 myoblasts occurs despite unaffected lysosomal pH, and although activation is further reduced by elevating lysosomal pH, it is partially restored by leucine supplementation. Overall, this study shows that lysosomal acid-α-glucosidase and acidity are required for activation of mTORC1 and that leucine partially restores mTORC1 activation that is reduced by an acid-α-glucosidase deficiency, elevated lysosomal pH, or both. |
