TY - JOUR
T1 - Prednisolone rescues Duchenne muscular dystrophy phenotypes in human pluripotent stem cell-derived skeletal muscle in vitro
AU - Al Tanoury, Ziad
AU - Zimmerman, John F.
AU - Rao, Jyoti
AU - Sieiro, Daniel
AU - McNamara, Harold M.
AU - Cherrier, Thomas
AU - Rodríguez-DelaRosa, Alejandra
AU - Hick-Colin, Aurore
AU - Bousson, Fanny
AU - Fugier-Schmucker, Charlotte
AU - Marchiano, Fabio
AU - Habermann, Bianca
AU - Chal, Jérome
AU - Nesmith, Alexander P.
AU - Gapon, Svetlana
AU - Wagner, Erica
AU - Gupta, Vandana A.
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
AU - Cohen, Adam E.
AU - Parker, Kevin Kit
AU - Pourquié, Olivier
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Lou Kunkel, Emanuela Gussoni, and Felipe Leite for critical reading of the manuscript and Suvi Aivio for technical help in the early stages of the project. We thank the NeuroTechnology Studio at Brigham and Women’s Hospital for providing InCell instrument access and consultation on data acquisition and data analysis. This work was supported by a strategic grant (17099) from the French Muscular Dystrophy Association (AFM), by an advanced grant (FP7-IDEAS-ERC-249931) from the European Research Council, by the FP7 EU grant Plurimes (602423), and by a Human Frontier Science Program award (RGP0052/2018) to O.P. and by an AFM postdoctoral grant (20581) to D.S. Additionally, this work was sponsored in part by the John A. Paulson School of Engineering and Applied Sciences at Harvard University, the Wyss Institute for Biologically Inspired Engineering at Harvard University, and Harvard Materials Research Science and Engineering Center grant DMR-1420570 to K.K.P. and an NIH Organ Design and Engineering postdoctoral training fellowship under T32EB016652 to J.F.Z., H.M.M., and A.E.C. were supported by the Howard Hughes Medical Institute. This work was supported in part by the Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center at University of Texas Southwestern Medical Center grant (HD087351) to E.N.O. B.H. and F.M. are supported by Agence Nationale de la Recherche (ANR) grant ANR-18-CE45-0016. This work was supported by the “la Caixa” Foundation (ID 100010434) under agreement LCF/BQ/AA18/11680032 to A.R.-d.l.R.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/7/13
Y1 - 2021/7/13
N2 - 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.
AB - 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.
KW - Duchenne muscular dystrophy
KW - Dystrophin
KW - Myogenesis
KW - Myopathy
KW - Pluripotent stem cell
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U2 - 10.1073/pnas.2022960118
DO - 10.1073/pnas.2022960118
M3 - Article
C2 - 34260377
AN - SCOPUS:85109428570
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 28
M1 - e2022960118
ER -