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Poster De Conférence Année : 2017

Consequences of ATP2A1 missplicing on muscle function

Résumé

"Introduction SERCA1 encoded by the ATP2A1 gene is involved in the excitation-contraction coupling and relaxation of the striated muscle by acting as one of the major Ca2+ ATPase responsible for the re-uptake of cytosolic Ca2+ into the sarcoplasmic reticulum. Developmental regulation of ATP2A1 exon 22 by alternative splicing leads to two distinct isoforms that are expressed either in adult (SERCA1a) or fetal (SERCA1b) tissues. This splicing switch modifies the C-terminus domain of SERCA1 but also ATPase and Ca2+ uptake activities, which are reduced for SERCA1b when compared to SERCA1a. ATP2A1 exon 22 is misspliced in affected muscles of DM1 patients however its consequence on skeletal muscle function is poorly understood. Methods/Results To investigate the impact of fetal SERCA1b re-expression in adult muscles, we propose to mimic ATP2A1 exon 22 missplicing in wild-type animal models using antisense approaches. An in vitro analysis using antisense oligonucleotides and splicing regulator factors was first performed to determine the more potent region/antisense sequence(s) allowing significant skipping of exon 22. Next, selected antisense sequences were cloned into a modified U7-snRNA cassette and vectorized in adeno-associated viral vectors. Currently, adult skeletal muscles of wt mice were transduced with theses AAV-U7 antisense vectors to determine their efficacy. In parallel, we used the ZebraFish model (Danio rerio) in which corresponding exon 22 is conserved and fully included one day post-fertilization. Antisense morpholinos were microinjected in 1-2 cell stage eggs and 2-5 day-old morphants were analyzed. Preliminary results show an exclusion of the corresponding exon 22 from and consequences at both physiological and morphological levels are under evaluation Conclusion This study should help us to better understand the consequences of abnormal SERCA1b re-expression on adult muscle function and its implication in DM1 pathophysiology."
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Dates et versions

hal-03999490 , version 1 (21-02-2023)

Identifiants

  • HAL Id : hal-03999490 , version 1

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Damily de Dea Diniz, Alain Sureau, Ludovic Arandel, Frederique Rau, Joelle Marie, et al.. Consequences of ATP2A1 missplicing on muscle function. International Myotonic Dystrophy Consortium Meeting IDMC-11, Sep 2017, San-Fransisco, United States. ⟨hal-03999490⟩
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