[MS10-4B-2] Modeling Infantile-onset Pompe Disease with Patient iPSCs Reveals Disturbed mTORC1 Signaling as an Early Pathogenesis of the Skeletal Muscle Damage
Pompe disease is a lysosomal storage disorder, caused by an inborn defect of acid α-glucosidase (GAA), and is characterized by lysosomal glycogen accumulation primarily in the skeletal muscle and heart. Patients with the severe type of the disease, infantile-onset Pompe disease (IOPD), show generalized muscle weakness and heart failure in early infancy, and cannot survive over two years. The only available treatment, enzyme replacement therapy with recombinant human GAA (rhGAA), significantly improves the survival rate of patients with IOPD. However, its effect on skeletal muscle is insufficient compared to other organs. Moreover, the patho-mechanism of skeletal muscle damage in IOPD has not been fully elucidated. To address these issues, we aimed to establish an efficient skeletal muscle model of IOPD. Here we generated induced pluripotent stem cells (iPSCs) from three patients with IOPD and differentiated them into myocytes. Differentiated myocytes showed lysosomal glycogen accumulation, the hallmark of Pompe disease, which was dose-dependently rescued by rhGAA treatment. Using our model, we demonstrated that mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity was impaired in myocytes derived from IOPD iPSCs. Furthermore, comprehensive metabolomic and transcriptomic analysis suggested the disturbance of mTORC1-related signaling, including deteriorated cellular energy status and suppressed mitochondrial oxidative function. In summary, we successfully established an in vitro skeletal muscle model of IOPD using patient-specific iPSCs. Disturbed mTORC1 signaling may contribute to the early pathogenesis of skeletal muscle damage in IOPD, and may be a potential therapeutic target for not only Pompe disease, but also whole lysosomal storage disorders.