Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology
McArdle disease is a rare autosomal recessive disorder caused by mutations in the <i>PYGM</i> gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/22/13964 |
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| author | María del Carmen Ortuño-Costela Victoria Cerrada Ana Moreno-Izquierdo Inés García-Consuegra Camille Laberthonnière Mégane Delourme Rafael Garesse Joaquín Arenas Carla Fuster García Gema García García José María Millán Frédérique Magdinier María Esther Gallardo |
| author_facet | María del Carmen Ortuño-Costela Victoria Cerrada Ana Moreno-Izquierdo Inés García-Consuegra Camille Laberthonnière Mégane Delourme Rafael Garesse Joaquín Arenas Carla Fuster García Gema García García José María Millán Frédérique Magdinier María Esther Gallardo |
| author_sort | María del Carmen Ortuño-Costela |
| collection | DOAJ |
| description | McArdle disease is a rare autosomal recessive disorder caused by mutations in the <i>PYGM</i> gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the <i>PYGM</i> gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of <i>PYGM</i> expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity. |
| first_indexed | 2024-03-09T18:17:16Z |
| format | Article |
| id | doaj.art-01480cb12c914ad5a69edeff24e3fe15 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:17:16Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-01480cb12c914ad5a69edeff24e3fe152023-11-24T08:36:21ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221396410.3390/ijms232213964Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC TechnologyMaría del Carmen Ortuño-Costela0Victoria Cerrada1Ana Moreno-Izquierdo2Inés García-Consuegra3Camille Laberthonnière4Mégane Delourme5Rafael Garesse6Joaquín Arenas7Carla Fuster García8Gema García García9José María Millán10Frédérique Magdinier11María Esther Gallardo12Grupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainGrupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainServicio de Genética, Hospital 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neuromusculares, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainAix-Marseille University, INSERM, MMG, 13385 Marseille, FranceAix-Marseille University, INSERM, MMG, 13385 Marseille, FranceDepartamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas “Alberto Sols”, (UAM-CSIC), 28029 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neuromusculares, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, SpainAix-Marseille University, INSERM, MMG, 13385 Marseille, FranceGrupo de Investigación Traslacional con células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainMcArdle disease is a rare autosomal recessive disorder caused by mutations in the <i>PYGM</i> gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the <i>PYGM</i> gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of <i>PYGM</i> expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity.https://www.mdpi.com/1422-0067/23/22/13964iPSCsMcArdle disease<i>PYGM</i>disease modellingskeletal muscle differentiationgene editing |
| spellingShingle | María del Carmen Ortuño-Costela Victoria Cerrada Ana Moreno-Izquierdo Inés García-Consuegra Camille Laberthonnière Mégane Delourme Rafael Garesse Joaquín Arenas Carla Fuster García Gema García García José María Millán Frédérique Magdinier María Esther Gallardo Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology International Journal of Molecular Sciences iPSCs McArdle disease <i>PYGM</i> disease modelling skeletal muscle differentiation gene editing |
| title | Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology |
| title_full | Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology |
| title_fullStr | Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology |
| title_full_unstemmed | Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology |
| title_short | Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology |
| title_sort | generation of the first human in vitro model for mcardle disease based on ipsc technology |
| topic | iPSCs McArdle disease <i>PYGM</i> disease modelling skeletal muscle differentiation gene editing |
| url | https://www.mdpi.com/1422-0067/23/22/13964 |
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