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Dis Model Mech. 2017 Apr 1;10(4):487-497. doi: 10.1242/dmm.027367. Epub 2017 Feb 10.

Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds.

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Sorbonne Universités UPMC Univ Paris 06, INSERM, CNRS, Centre de Recherche en Myologie, Institut de Myologie, GH Pitié-Salpêtrière, Paris 75013, France.
McMaster University Medical Center, Departments of Pediatrics and Medicine, 1200 Main St W., Hamilton, Ontario, Canada, L8N 3Z5.
CHU de Quebec, site Enfant-Jésus, Université Laval, Québec, Canada G1J 1Z4.
Centre National de Génotypage, Institut de Génomique, CEA, 91000 Evry, France.
Sorbonne Universités UPMC Univ Paris 06, INSERM, CNRS, Centre de Recherche en Myologie, Institut de Myologie, GH Pitié-Salpêtrière, Paris 75013, France


Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations.


Alternative splicing; Expanded repeats; Muscle cell line; Myotonic dystrophy; Nuclear aggregates; Therapeutic compounds

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