Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts
Duchenne muscular dystrophy (DMD) affects myofibers and muscle stem cells, causing progressive muscle degeneration and repair defects. It was unknown whether dystrophic myoblasts—the effector cells of muscle growth and regeneration—are affected. Using transcriptomic, genome-scale metabolic modelling...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/75521 |
| _version_ | 1818016521853599744 |
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| author | Maxime RF Gosselin Virginie Mournetas Malgorzata Borczyk Suraj Verma Annalisa Occhipinti Justyna Róg Lukasz Bozycki Michal Korostynski Samuel C Robson Claudio Angione Christian Pinset Dariusz C Gorecki |
| author_facet | Maxime RF Gosselin Virginie Mournetas Malgorzata Borczyk Suraj Verma Annalisa Occhipinti Justyna Róg Lukasz Bozycki Michal Korostynski Samuel C Robson Claudio Angione Christian Pinset Dariusz C Gorecki |
| author_sort | Maxime RF Gosselin |
| collection | DOAJ |
| description | Duchenne muscular dystrophy (DMD) affects myofibers and muscle stem cells, causing progressive muscle degeneration and repair defects. It was unknown whether dystrophic myoblasts—the effector cells of muscle growth and regeneration—are affected. Using transcriptomic, genome-scale metabolic modelling and functional analyses, we demonstrate, for the first time, convergent abnormalities in primary mouse and human dystrophic myoblasts. In Dmdmdx myoblasts lacking full-length dystrophin, the expression of 170 genes was significantly altered. Myod1 and key genes controlled by MyoD (Myog, Mymk, Mymx, epigenetic regulators, ECM interactors, calcium signalling and fibrosis genes) were significantly downregulated. Gene ontology analysis indicated enrichment in genes involved in muscle development and function. Functionally, we found increased myoblast proliferation, reduced chemotaxis and accelerated differentiation, which are all essential for myoregeneration. The defects were caused by the loss of expression of full-length dystrophin, as similar and not exacerbated alterations were observed in dystrophin-null Dmdmdx-βgeo myoblasts. Corresponding abnormalities were identified in human DMD primary myoblasts and a dystrophic mouse muscle cell line, confirming the cross-species and cell-autonomous nature of these defects. The genome-scale metabolic analysis in human DMD myoblasts showed alterations in the rate of glycolysis/gluconeogenesis, leukotriene metabolism, and mitochondrial beta-oxidation of various fatty acids. These results reveal the disease continuum: DMD defects in satellite cells, the myoblast dysfunction affecting muscle regeneration, which is insufficient to counteract muscle loss due to myofiber instability. Contrary to the established belief, our data demonstrate that DMD abnormalities occur in myoblasts, making these cells a novel therapeutic target for the treatment of this lethal disease. |
| first_indexed | 2024-04-14T07:13:31Z |
| format | Article |
| id | doaj.art-6e98c057ed4b4500b5bfe008d1e51f41 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:13:31Z |
| publishDate | 2022-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-6e98c057ed4b4500b5bfe008d1e51f412022-12-22T02:06:21ZengeLife Sciences Publications LtdeLife2050-084X2022-09-011110.7554/eLife.75521Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblastsMaxime RF Gosselin0https://orcid.org/0000-0002-8916-0953Virginie Mournetas1https://orcid.org/0000-0002-6557-4190Malgorzata Borczyk2Suraj Verma3Annalisa Occhipinti4Justyna Róg5Lukasz Bozycki6Michal Korostynski7Samuel C Robson8https://orcid.org/0000-0001-5702-9160Claudio Angione9https://orcid.org/0000-0002-3140-7909Christian Pinset10Dariusz C Gorecki11https://orcid.org/0000-0003-3584-1654School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United KingdomINSERM UEVE UMR861, I-STEM, AFM, Corbeil-Essonnes, FranceLaboratory of Pharmacogenomics, Maj Institute of Pharmacology PAS, Krakow, PolandSchool of Computing, Engineering and Digital Technologies, Teesside University, Middlesbrough, United KingdomSchool of Computing, Engineering and Digital Technologies, Teesside University, Middlesbrough, United KingdomSchool of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom; Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Warsaw, PolandSchool of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom; Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Warsaw, PolandLaboratory of Pharmacogenomics, Maj Institute of Pharmacology PAS, Krakow, PolandSchool of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom; Centre for Enzyme Innovation, University of Portsmouth, Portsmouth, United KingdomSchool of Computing, Engineering and Digital Technologies, Teesside University, Middlesbrough, United KingdomCNRS, I-STEM, AFM, Corbeil-Essonnes, FranceSchool of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United KingdomDuchenne muscular dystrophy (DMD) affects myofibers and muscle stem cells, causing progressive muscle degeneration and repair defects. It was unknown whether dystrophic myoblasts—the effector cells of muscle growth and regeneration—are affected. Using transcriptomic, genome-scale metabolic modelling and functional analyses, we demonstrate, for the first time, convergent abnormalities in primary mouse and human dystrophic myoblasts. In Dmdmdx myoblasts lacking full-length dystrophin, the expression of 170 genes was significantly altered. Myod1 and key genes controlled by MyoD (Myog, Mymk, Mymx, epigenetic regulators, ECM interactors, calcium signalling and fibrosis genes) were significantly downregulated. Gene ontology analysis indicated enrichment in genes involved in muscle development and function. Functionally, we found increased myoblast proliferation, reduced chemotaxis and accelerated differentiation, which are all essential for myoregeneration. The defects were caused by the loss of expression of full-length dystrophin, as similar and not exacerbated alterations were observed in dystrophin-null Dmdmdx-βgeo myoblasts. Corresponding abnormalities were identified in human DMD primary myoblasts and a dystrophic mouse muscle cell line, confirming the cross-species and cell-autonomous nature of these defects. The genome-scale metabolic analysis in human DMD myoblasts showed alterations in the rate of glycolysis/gluconeogenesis, leukotriene metabolism, and mitochondrial beta-oxidation of various fatty acids. These results reveal the disease continuum: DMD defects in satellite cells, the myoblast dysfunction affecting muscle regeneration, which is insufficient to counteract muscle loss due to myofiber instability. Contrary to the established belief, our data demonstrate that DMD abnormalities occur in myoblasts, making these cells a novel therapeutic target for the treatment of this lethal disease.https://elifesciences.org/articles/75521DMDdystrophinmyoblasttranscriptomicsmdx |
| spellingShingle | Maxime RF Gosselin Virginie Mournetas Malgorzata Borczyk Suraj Verma Annalisa Occhipinti Justyna Róg Lukasz Bozycki Michal Korostynski Samuel C Robson Claudio Angione Christian Pinset Dariusz C Gorecki Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts eLife DMD dystrophin myoblast transcriptomics mdx |
| title | Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts |
| title_full | Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts |
| title_fullStr | Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts |
| title_full_unstemmed | Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts |
| title_short | Loss of full-length dystrophin expression results in major cell-autonomous abnormalities in proliferating myoblasts |
| title_sort | loss of full length dystrophin expression results in major cell autonomous abnormalities in proliferating myoblasts |
| topic | DMD dystrophin myoblast transcriptomics mdx |
| url | https://elifesciences.org/articles/75521 |
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