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

Area of Science:

• Biochemistry
• Genetics
• Cell Biology

Background:

• Pompe disease results from acid α-glucosidase (GAA) deficiency, causing glycogen accumulation in lysosomes, primarily affecting skeletal and cardiac muscles.
• Infantile-onset Pompe disease (IOPD) presents with severe muscle weakness and heart failure, leading to early mortality, with enzyme replacement therapy showing limited skeletal muscle efficacy.
• The precise mechanisms underlying skeletal muscle pathology in IOPD remain incompletely understood.

Purpose of the Study:

• To establish a patient-specific in vitro model for studying skeletal muscle damage in IOPD.
• To investigate the molecular mechanisms contributing to skeletal muscle pathology in IOPD.
• To identify potential therapeutic targets for IOPD.

Main Methods:

• Generation of induced pluripotent stem cells (iPSCs) from IOPD patients.
• Differentiation of iPSCs into myocytes.
• Assessment of lysosomal glycogen accumulation and rescue by recombinant human GAA (rhGAA).
• Analysis of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity.
• Comprehensive metabolomic and transcriptomic analyses.

Main Results:

• IOPD iPSC-derived myocytes exhibited lysosomal glycogen accumulation, which was responsive to rhGAA treatment in a dose-dependent manner.
• Impaired mTORC1 activity was observed in IOPD iPSC-derived myocytes.
• Metabolomic and transcriptomic data indicated mTORC1-related signaling disturbances, including compromised energy status and reduced mitochondrial oxidative function.

Conclusions:

• A patient-specific iPSC-derived skeletal muscle model for IOPD was successfully developed.
• Disrupted mTORC1 signaling is implicated in the pathogenesis of skeletal muscle damage in IOPD.
• Targeting mTORC1 signaling presents a potential therapeutic strategy for Pompe disease.