Dataset Information

A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells.

ABSTRACT: Pompe disease is caused by an inborn defect of lysosomal acid ?-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. They cannot survive over two years. Enzyme replacement therapy with recombinant human GAA (rhGAA) improves the survival rate, but its effect on skeletal muscle is insufficient compared to other organs. Moreover, the patho-mechanism of skeletal muscle damage in IOPD is still unclear. Here we generated induced pluripotent stem cells (iPSCs) from patients with IOPD and differentiated them into myocytes. Differentiated myocytes showed lysosomal glycogen accumulation, which was dose-dependently rescued by rhGAA. We further demonstrated that mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity was impaired in IOPD iPSC-derived myocytes. Comprehensive metabolomic and transcriptomic analyses suggested the disturbance of mTORC1-related signaling, including deteriorated 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 pathogenesis of skeletal muscle damage in IOPD, and may be a potential therapeutic target for Pompe disease.

SUBMITTER: Yoshida T

PROVIDER: S-EPMC5647434 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells.

Yoshida Takeshi T Awaya Tomonari T Jonouchi Tatsuya T Kimura Ryo R Kimura Shigemi S Era Takumi T Heike Toshio T Sakurai Hidetoshi H

Scientific reports 20171018 1

Pompe disease is caused by an inborn defect of lysosomal 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. They cannot survive over two years. Enzyme replacement therapy with recombinant human GAA (rhGAA) improves the survival rate, but its effect on skeletal muscle is in ...[more]

PMID: 29044175

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Project description:BackgroundPompe disease is an autosomal recessive metabolic neuromuscular disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It has long been believed that the underlying pathology leading to tissue damage is caused by the enlargement and rupture of glycogen-filled lysosomes. Recent studies have also implicated autophagy, an intracellular lysosome-dependent degradation system, in the disease pathogenesis. In this study, we characterize the long-term impact of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) on lysosomal glycogen accumulation and autophagy in some of the oldest survivors with classic infantile Pompe disease (IPD).MethodsMuscle biopsies from 8 [4 female, 4 male; 6 cross-reactive immunologic material (CRIM)-positive, 2 CRIM-negative] patients with a confirmed diagnosis of classic IPD were examined using standard histopathological approaches. In addition, muscle biopsies were evaluated by immunostaining for lysosomal marker (lysosomal-associated membrane protein-2; LAMP2), autophagosomal marker (microtubule-associated protein 1 light chain 3; LC3), and acid and alkaline ATPases. All patients received rhGAA by infusion at cumulative biweekly doses of 20-40 mg/kg.ResultsMedian age at diagnosis of classic IPD was 3.4 months (range: 0 to 6.5 months; n = 8). At the time of muscle biopsy, the patients' ages ranged from 1 to 103 months and ERT duration ranged from 0 (i.e., baseline, pre-ERT) to 96 months. The response to therapy varied considerably among the patients: some patients demonstrated motor gains while others experienced deterioration of motor function, either with or without a period of initial clinical benefit. Skeletal muscle pathology included fiber destruction, lysosomal vacuolation, and autophagic abnormalities (i.e., buildup), particularly in fibers with minimal lysosomal enlargement. Overall, the pathology reflected clinical status.ConclusionsThis is the first study to investigate the impact of rhGAA ERT on lysosomal glycogen accumulation and autophagic buildup in patients with classic IPD beyond 18 months of treatment. Our findings indicate that ERT does not fully halt or reverse the underlying skeletal muscle pathology in IPD. The best outcomes were observed in the two patients who began therapy early, namely at 0.5 and 1.1 months of age.

Project description:Infantile onset Pompe disease (IOPD) is a rare and lethal genetic disorder caused by the deletion of the acid alpha-glucosidase (GAA) gene. This gene encodes an essential lysosomal enzyme that converts glycogen to glucose. While enzyme replacement therapy helps some, our understanding of disease pathophysiology is limited. In this project we develop computer simulated stem cells (aiPSC) and differentiated skeletal muscle cells (aiSkMC) to empower IOPD research and drug discovery. Our Artificial Intelligence (AI) platform, DeepNEU v3.6 was used to generate aiPSC and aiSkMC simulations with and without GAA expression. These simulations were validated using peer reviewed results from the recent literature. Once the aiSkMC simulations (IOPD and WT) were validated they were used to evaluate calcium homeostasis and mitochondrial function in IOPD. Lastly, we used aiSkMC IOPD simulations to identify known and novel biomarkers and potential therapeutic targets. The aiSkMC simulations of IOPD correctly predicted genotypic and phenotypic features that were reported in recent literature. The probability that these features were accurately predicted by chance alone using the binomial test is 0.0025. The aiSkMC IOPD simulation correctly identified L-type calcium channels (VDCC) as a biomarker and confirmed the positive effects of calcium channel blockade (CCB) on calcium homeostasis and mitochondrial function. These published data were extended by the aiSkMC simulations to identify calpain(s) as a novel potential biomarker and therapeutic target for IOPD. This is the first time that computer simulations of iPSC and differentiated skeletal muscle cells have been used to study IOPD. The simulations are robust and accurate based on available published literature. We also demonstrated that the IOPD simulations can be used for potential biomarker identification leading to targeted drug discovery. We will continue to explore the potential for calpain inhibitors with and without CCB as effective therapy for IOPD.

Dataset Information

A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells.

Publications

A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells.

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