Prednisolone rescues Duchenne Muscular Dystrophy phenotypes in human pluripotent stem cells-derived skeletal muscle in vitro

Duchenne Muscular Dystrophy (DMD) is a devastating genetic disease leading to degeneration of skeletal muscles and premature death. How dystrophin absence leads to muscle wasting remains unclear. Here, we describe an optimized protocol to differentiate human induced Pluripotent Stem Cells (iPSC) to...

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Published inbioRxiv
Main Authors Ziad Al Tanoury, Zimmermann, John F, Rao, Jyoti, Sieiro, Daniel, Mcnamara, Harry, Cherrier, Thomas, Hick, Aurore, Bousson, Fanny, Fugier, Charlotte, Marchiano, Fabio, Habermann, Bianca, Chal, Jérome, Nesmith, Alexander P, Gapon, Svetlana, Wagner, Erica, Bassel-Duby, Rhonda, Olson, Eric, Cohen, Adam E, Parker, Kevin Kit, Pourquié, Olivier
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 29.10.2020
Subjects
Anti-inflammatory agents
Calcium
Cell differentiation
Contraction
Degeneration
Duchenne's muscular dystrophy
Dystrophin
Inflammation
Muscular dystrophy
Phenotypes
Pluripotency
Prednisolone
Skeletal muscle
Stem cells
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Summary:Duchenne Muscular Dystrophy (DMD) is a devastating genetic disease leading to degeneration of skeletal muscles and premature death. How dystrophin absence leads to muscle wasting remains unclear. Here, we describe an optimized protocol to differentiate human induced Pluripotent Stem Cells (iPSC) to a late myogenic stage. This allows to recapitulate classical DMD phenotypes (mislocalization of proteins of the Dystrophin-glycoprotein associated complex (DGC), increased fusion, myofiber branching, force contraction defects and calcium hyperactivation) in isogenic DMD-mutant iPSC lines in vitro. Treatment of the myogenic cultures with prednisolone (the standard of care for DMD) can dramatically rescue force contraction, fusion and branching defects in DMD iPSC lines. This argues that prednisolone acts directly on myofibers, challenging the largely prevalent view that its beneficial effects are due to anti-inflammatory properties. Our work introduces a new human in vitro model to study the onset of DMD pathology and test novel therapeutic approaches. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.10.29.360826