Three-dimensional tissue-engineered human skeletal muscle model of Pompe disease
| Autor: | Dwight D. Koeberl, Sabrina Tran, Chris J. Zhou, Alastair Khodabukus, Lauran Madden, Aaron L. Carlson, Priya S. Kishnani, Jason Wang, Nenad Bursac, Sang-oh Han |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty QH301-705.5 Metabolic disorders Medicine (miscellaneous) Muscle Development Article General Biochemistry Genetics and Molecular Biology Virus Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Lysosome medicine Animals Biology (General) Muscle Skeletal Mice Knockout Tissue Engineering Glycogen Glycogen Storage Disease Type II business.industry Myocardium Cardiac muscle Skeletal muscle alpha-Glucosidases Enzyme replacement therapy Dependovirus Pathophysiology In vitro Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Musculoskeletal models Lysosomes General Agricultural and Biological Sciences business 030217 neurology & neurosurgery Muscle Contraction |
| Zdroj: | Communications Biology, Vol 4, Iss 1, Pp 1-14 (2021) Communications Biology |
| ISSN: | 2399-3642 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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