Three-dimensional tissue-engineered human skeletal muscle model of Pompe disease

• Published in: Communications biology 2021-05, Vol.4 (1), p.524-14, Article 524
• Main Authors: Wang, Jason, Zhou, Chris J., Khodabukus, Alastair, Tran, Sabrina, Han, Sang-Oh, Carlson, Aaron L., Madden, Lauran, Kishnani, Priya S., Koeberl, Dwight D., Bursac, Nenad
• Format: Article
• Language: English
• Subjects: 13/107; 14/19; 631/1647/767/2200; 692/699/317; 96/31; 96/35; alpha-Glucosidases - administration & dosage; alpha-Glucosidases - genetics; alpha-Glucosidases - metabolism; Animals; Biology; Biomedical and Life Sciences; Cardiac muscle; Dependovirus - genetics; Disease Models, Animal; Enzymatic activity; Enzymes; Glycogen; Glycogen - metabolism; Glycogen Storage Disease Type II - metabolism; Glycogen Storage Disease Type II - pathology; Glycogen Storage Disease Type II - therapy; Life Sciences; Lysosomes - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction; Muscle Development; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Musculoskeletal system; Myocardium - cytology; Myocardium - metabolism; Pathophysiology; Quadriceps muscle; Sequence analysis; Skeletal muscle; Tissue engineering; Tissue Engineering - methods; Transcription; Transcriptomics; α-Glucosidase
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02059-4

In Pompe disease, the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) causes skeletal and cardiac muscle weakness, respiratory failure, and premature death. While enzyme replacement therapy using recombinant human GAA (rhGAA) can significantly improve patient outcomes, detailed disease mechanisms and incomplete therapeutic effects require further studies. Here we report a three-dimensional primary human skeletal muscle (“myobundle”) model of infantile-onset Pompe disease (IOPD) that recapitulates hallmark pathological features including reduced GAA enzyme activity, elevated glycogen content and lysosome abundance, and increased sensitivity of muscle contractile function to metabolic stress. In vitro treatment of IOPD myobundles with rhGAA or adeno-associated virus (AAV)-mediated hGAA expression yields increased GAA activity and robust glycogen clearance, but no improvements in stress-induced functional deficits. We also apply RNA sequencing analysis to the quadriceps of untreated and AAV-treated GAA −/− mice and wild-type controls to establish a Pompe disease-specific transcriptional signature and reveal novel disease pathways. The mouse-derived signature is enriched in the transcriptomic profile of IOPD vs. healthy myobundles and partially reversed by in vitro rhGAA treatment, further confirming the utility of the human myobundle model for studies of Pompe disease and therapy. Wang et al. describe the development of a 3D in vitro model of human skeletal muscle that recapitulates the pathophysiology of Pompe disease. They further define a Pompe disease-specific transcriptional signature, confirm its presence in the Pompe myobundles, and detect a partial reversal of the signature upon in vitro treatment of myobundles with rhGAA.