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Resveratrol corrects aberrant splicing of RYR1 pre-mRNA and Ca2+ signal in myotonic dystrophy type 1 myotubes

Neural Regeneration Research 2020年第9期15卷 1757-1766页

作者： Massimo Santoro Roberto Piacentini Alessia Perna eugenia pisano Anna Severino Anna Modoni Claudio Grassi Gabriella Silvestri IRCCS Fondazione Don Carlo Gnocchi MilanItaly Department of Neuroscience Universita Cattolica del Sacro CuoreRomeItaly Department of Cardiovascular and Thoracic Sciences Universita Cattolica del Sacro CuoreRomeItaly Fondazione Policlinico Universitario A.Gemelli IRCCS RomeItaly

Myotonic dystrophy type 1(DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1(RYR1), sarcoplasmatic/endoplasmatic Ca^2+-ATPase(SERCA) and α1 S subunit of voltage-gated Ca^2+ channels(Cav1.1) is related to Ca^2+ homeostasis and excitation-contraction coupling impairment. Though no pharmacological treatment for DM1 exists, aberrant splicing correction represents one major therapeutic target for this disease. Resveratrol(RES, 3,5,4′-trihydroxy-trans-stilbene) is a promising pharmacological tools for DM1 treatment for its ability to directly bind the DNA and RNA influencing gene expression and alternative splicing. Herein, we analyzed the therapeutic effects of RES in DM1 myotubes in a pilot study including cultured myotubes from two DM1 patients and two healthy controls. Our results indicated that RES treatment corrected the aberrant splicing of RYR1, and this event appeared associated with restoring of depolarization-induced Ca^2+ release from RYR1 dependent on the electro-mechanical coupling between RYR1 and Cav1.1. Interestingly, immunoblotting studies showed that RES treatment was associated with a reduction in the levels of CUGBP Elav-like family member 1, while RYR1, Cav1.1 and SERCA1 protein levels were unchanged. Finally, RES treatment did not induce any major changes either in the amount of ribonuclear foci or sequestration of muscleblind-like splicing regulator 1. Overall, the results of this pilot study would support RES as an attractive compound for future clinical trials in DM1. Ethical approval was obtained from the Ethical Committee of IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy(rs9879/14) on May 20, 2014.

关键词： alternative splicing calcium homeostasis CUG-BP1 foci MBNL1 myotonic dystrophy type 1 myotubes resveratrol

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