Prednisolone rescues Duchenne muscular dystrophy phenotypes in human pluripotent stem cell–derived skeletal muscle in vitro
Year: 2021
Type: article
Abstract: 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 us to recapitulate classical DMD phenotypes (mislocalization of proteins of the dystrophin-associated glycoprotein complex, 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 caused by antiinflammatory properties. Our work introduces a human in vitro model to study the onset of DMD pathology and test novel therapeutic approaches.
Authors: Ziad Al Tanoury, John F. Zimmerman, Jyoti Rao, Daniel Sieiro, Harold M. McNamara, Thomas Cherrier, Alejandra Rodríguez-delaRosa, Aurore Hick-Colin, Fanny Bousson, Charlotte Fugier-Schmucker, Fabio Marchiano, Bianca Habermann, Jérome Chal, Alexander P. Nesmith, Svetlana Gapon, Erica Wagner, Vandana A. Gupta, Rhonda Bassel-Duby, Eric N. Olson, Adam E. Cohen, Kevin Kit Parker, Olivier Pourquié
Institutions: Brigham and Women's Hospital, Centre National de la Recherche Scientifique, Harvard University, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, Harvard Stem Cell Institute, Université de Strasbourg, Wyss Institute for Biologically Inspired Engineering, Aix-Marseille Université, Institut de Biologie du Développement Marseille, The University of Texas Southwestern Medical Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, Human Frontier Science Program, Muscular Dystrophy Association, Harvard University, University of Texas Southwestern Medical Center, “la Caixa” Foundation, French Muscular Dystrophy Association, European Commission, Agence Nationale de la Recherche, AFM-Téléthon, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, Materials Research Science and Engineering Center, Harvard University, Hansjörg Wyss Institute for Biologically Inspired Engineering, Harvard University, National Institute of Biomedical Imaging and Bioengineering, Division of Materials Research, Office of Extramural Research, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, FP7 Ideas: European Research Council, FP7 Health
Awards: G1020486556, Systematic functional analysis of mitochondrial dynamics in healthy young, aged and sarcopenic muscle, G2254063607, G2553460746, G2678829282, G2981753094, Myoediting of Duchenne Muscular Dystrophy, G3150353937, Pluripotent stem cell resources for mesodermal medicine, G3366412161, G3953734904, G4220372196, G4656594441, G508112437, Organ Design and Engineering Training Program (ODET Program), G6698385514, G6812258478, Muscle building: dissecting tension-driven myofibrillogenesis in vitro, in vivo and in silico, G8925751364, Myoediting of Duchenne muscular dystrophy
OpenAlex ID: W3127124593