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Myogenesis modelled by human pluripotent stem cells uncovers Duchenne muscular dystrophy phenotypes prior to skeletal muscle commitment

Mournetas, Virginie and Massouridès, Emmanuelle and Dupont, Jean-Baptiste and Kornobis, Etienne and Polvèche, Hélène and Jarrige, Margot and Gosselin, Maxime R. F. and Manousopoulou, Antigoni and Garbis, Spiros D. and Górecki, Dariusz C. and Pinset, Christian (2020) Myogenesis modelled by human pluripotent stem cells uncovers Duchenne muscular dystrophy phenotypes prior to skeletal muscle commitment. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20200415-091757013

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Abstract

Duchenne muscular dystrophy (DMD) causes severe disability of children and death of young men, with an incidence of approximately 1/5,000 male births. Symptoms appear in early childhood, with a diagnosis made around 4 years old, a time where the amount of muscle damage is already significant, preventing early therapeutic interventions that could be more efficient at halting disease progression. In the meantime, the precise moment at which disease phenotypes arise - even asymptomatically - is still unknown. Thus, there is a critical need to better define DMD onset as well as its first manifestations, which could help identify early disease biomarkers and novel therapeutic targets. In this study, we have used human induced pluripotent stem cells (hiPSCs) from DMD patients to model skeletal myogenesis, and compared their differentiation dynamics to healthy control cells by a comprehensive multi-omics analysis. Transcriptome and miRnome comparisons combined with protein analyses at 7 time points demonstrate that hiPSC differentiation 1) mimics described DMD phenotypes at the differentiation endpoint; and 2) homogeneously and robustly recapitulates key developmental steps - mesoderm, somite, skeletal muscle - which offers the possibility to explore dystrophin functions and find earlier disease biomarkers. Starting at the somite stage, mitochondrial gene dysregulations escalate during differentiation. We also describe fibrosis as an intrinsic feature of skeletal muscle cells that starts early during myogenesis. In sum, our data strongly argue for an early developmental manifestation of DMD whose onset is triggered before the entry into the skeletal muscle compartment, data leading to a necessary reconsideration of dystrophin functions during muscle development.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/720920DOIDiscussion Paper
ORCID:
AuthorORCID
Mournetas, Virginie0000-0002-6557-4190
Massouridès, Emmanuelle0000-0002-9829-5008
Dupont, Jean-Baptiste0000-0001-5706-8178
Kornobis, Etienne0000-0001-7712-8270
Gosselin, Maxime R. F.0000-0003-0870-2130
Manousopoulou, Antigoni0000-0001-5028-1865
Garbis, Spiros D.0000-0002-1050-0805
Pinset, Christian0000-0002-7840-2179
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. Posted April 14, 2020. The RNA-Sequencing libraries were processed and sequenced by Integragen (Evry, France). We gratefully acknowledge support from the PSMN (Pôle Scientifique de Modélisation Numérique) of the ENS de Lyon for the computing resources. We thank Dr Nacira Tabti, Dr Elisabeth Le Rumeur, Dr Nathalie Deburgrave and Dr Malgorzata Rak for providing us with specific reagents and antibodies. We thank Dr Linda Popplewell for designing and validating the PMO7 sequence. We thank Dr David Israeli for his feedback on the manuscript and overall discussion on our project. The authors declare that they have no competing interests. We thank the Fondation Maladies Rares (GenOmics grant), Labex Revive (Investissement d’Avenir; ANR-10-LABX-73) and the AFM Téléthon for funding this project.
Funders:
Funding AgencyGrant Number
Fondation Maladies RaresUNSPECIFIED
Agence Nationale pour la Recherche (ANR)ANR-10-LABX-73
AFM TéléthonUNSPECIFIED
Record Number:CaltechAUTHORS:20200415-091757013
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200415-091757013
Official Citation:Myogenesis modelled by human pluripotent stem cells uncovers Duchenne muscular dystrophy phenotypes prior to skeletal muscle commitment. Virginie Mournetas, Emmanuelle Massourides, Jean-Baptiste Dupont, Etienne Kornobis, Helene Polveche, Margot Jarrige, Maxime R. F. Gosselin, Antigoni Manousopoulou, Spiros D. Garbis, Dariusz C. Gorecki, Christian Pinset. bioRxiv 720920; doi: https://doi.org/10.1101/720920
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102550
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:15 Apr 2020 16:30
Last Modified:15 Apr 2020 16:30

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