MiR-23b and MiR-218 Silencing Increase Muscleblind-like Expression and Alleviate Myotonic Dystrophy Phenotypes in Mammalian Models

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Jun 28

PMID 29946070

Citations 42

Authors

Estefania Cerro-Herreros

Maria Sabater-Arcis

Juan M Fernandez-Costa

Nerea Moreno

Manuel Perez-Alonso

Beatriz Llamusi

Ruben Artero

Affiliations

Soon will be listed here.

Abstract

Functional depletion of the alternative splicing factors Muscleblind-like (MBNL 1 and 2) is at the basis of the neuromuscular disease myotonic dystrophy type 1 (DM1). We previously showed the efficacy of miRNA downregulation in Drosophila DM1 model. Here, we screen for miRNAs that regulate MBNL1 and MBNL2 in HeLa cells. We thus identify miR-23b and miR-218, and confirm that they downregulate MBNL proteins in this cell line. Antagonists of miR-23b and miR-218 miRNAs enhance MBNL protein levels and rescue pathogenic missplicing events in DM1 myoblasts. Systemic delivery of these "antagomiRs" similarly boost MBNL expression and improve DM1-like phenotypes, including splicing alterations, histopathology, and myotonia in the HSA DM1 model mice. These mammalian data provide evidence for therapeutic blocking of the miRNAs that control Muscleblind-like protein expression in myotonic dystrophy.

Citing Articles

Use of HSA female mice as a model for the study of myotonic dystrophy type I.

Carrascosa-Saez M, Colom-Rodrigo A, Gonzalez-Martinez I, Perez-Gomez R, Garcia-Rey A, Piqueras-Losilla D Lab Anim (NY). 2025; .

PMID: 40016516 DOI: 10.1038/s41684-025-01506-7.

Functions of the Muscleblind-like protein family and their role in disease.

Zhou H, Xu J, Pan L Cell Commun Signal. 2025; 23(1):97.

PMID: 39966885 PMC: 11837677. DOI: 10.1186/s12964-025-02102-5.

Alternative splicing dysregulation across tissue and therapeutic approaches in a mouse model of myotonic dystrophy type 1.

Hicks S, Frias J, Mishra S, Scotti M, Muscato D, Valero M Mol Ther Nucleic Acids. 2024; 35(4):102338.

PMID: 39391766 PMC: 11465180. DOI: 10.1016/j.omtn.2024.102338.

AntimiR treatment corrects myotonic dystrophy primary cell defects across several CTG repeat expansions with a dual mechanism of action.

Cerro-Herreros E, Nunez-Manchon J, Naldaiz-Gastesi N, Carrascosa-Saez M, Garcia-Rey A, Losilla D Sci Adv. 2024; 10(41):eadn6525.

PMID: 39383229 PMC: 11463307. DOI: 10.1126/sciadv.adn6525.

MBNL splicing factors regulate the microtranscriptome of skeletal muscles.

Piasecka A, Szczesniak M, Sekrecki M, Kajdasz A, Sznajder L, Baud A Nucleic Acids Res. 2024; 52(19):12055-12073.

PMID: 39258536 PMC: 11514471. DOI: 10.1093/nar/gkae774.

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