Identification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles.

5' Untranslated Regions / genetics Animals Betaxolol / pharmacology Cell Line Disease Models, Animal Drug Evaluation, Preclinical Drug Repositioning Humans Internal Ribosome Entry Sites / genetics Mice Mice, Inbred mdx Mice, Knockout Muscular Dystrophy, Duchenne / drug therapy Myoblasts Peptide Elongation Factor 1 / antagonists & inhibitors Pravastatin / pharmacology Protein Biosynthesis / drug effects Up-Regulation / drug effects Utrophin / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
24 04 2020
Historique:
received: 02 04 2019
accepted: 06 04 2020
entrez: 26 4 2020
pubmed: 26 4 2020
medline: 11 8 2020
Statut: epublish

Résumé

Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5'UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway.

Identifiants

DOI: 10.1038/s41467-020-15971-w PMID: 32332749 PMC: PMC7181625
pubmed: 32332749
doi: 10.1038/s41467-020-15971-w
pii: 10.1038/s41467-020-15971-w
pmc: PMC7181625
doi:

Substances chimiques

5' Untranslated Regions 0
EEF1A2 protein, human 0
Eef1a2 protein, mouse 0
Internal Ribosome Entry Sites 0
Peptide Elongation Factor 1 0
UTRN protein, human 0
Utrn protein, mouse 0
Utrophin 0
Pravastatin KXO2KT9N0G
Betaxolol O0ZR1R6RZ2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1990

Subventions

Organisme : CIHR
Pays : Canada

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Auteurs

Christine Péladeau (C)

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Centre for Neuromuscular Disease, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.

Nadine Adam (N)

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Centre for Neuromuscular Disease, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.

Lucas M Bronicki (LM)

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Centre for Neuromuscular Disease, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.

Adèle Coriati (A)

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.

Mohamed Thabet (M)

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.

Hasanen Al-Rewashdy (H)

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Centre for Neuromuscular Disease, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.

Jason Vanstone (J)

Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 5B2, Canada.
ORCID: 0000-0001-8411-2664

Alan Mears (A)

Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 5B2, Canada.

Jean-Marc Renaud (JM)

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.

Martin Holcik (M)

Department of Health Sciences, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.

Bernard J Jasmin (BJ)

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. jasmin@uottawa.ca.
Centre for Neuromuscular Disease, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. jasmin@uottawa.ca.

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questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Identification of therapeutics that target...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Dystrophies musculaires › Myopathie de Duchenne › Identification of therapeutics that target...
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