Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies.
Adaptor Proteins, Signal Transducing
/ antagonists & inhibitors
Animals
Disease Models, Animal
Dynamin II
/ antagonists & inhibitors
Gene Expression Profiling
/ methods
Humans
Longitudinal Studies
Mass Spectrometry
Mice
Myopathies, Structural, Congenital
/ drug therapy
Nerve Tissue Proteins
/ antagonists & inhibitors
Oligonucleotides, Antisense
/ therapeutic use
Protein Tyrosine Phosphatases, Non-Receptor
/ genetics
Proteomics
/ methods
Sequence Analysis, RNA
Tamoxifen
/ therapeutic use
Tumor Suppressor Proteins
/ antagonists & inhibitors
MTM1
RNA interference
XLMTM
biomarker
centronuclear myopathy
congenital myopathy
genetic disease
myostatin
myotubular myopathy
myotubularin
omics
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
04 08 2021
04 08 2021
Historique:
received:
08
02
2021
revised:
09
04
2021
accepted:
27
04
2021
pubmed:
4
5
2021
medline:
5
2
2022
entrez:
3
5
2021
Statut:
ppublish
Résumé
Omics analyses are powerful methods to obtain an integrated view of complex biological processes, disease progression, or therapy efficiency. However, few studies have compared different disease forms and different therapy strategies to define the common molecular signatures representing the most significant implicated pathways. In this study, we used RNA sequencing and mass spectrometry to profile the transcriptomes and proteomes of mouse models for three forms of centronuclear myopathies (CNMs), untreated or treated with either a drug (tamoxifen), antisense oligonucleotides reducing the level of dynamin 2 (DNM2), or following modulation of DNM2 or amphiphysin 2 (BIN1) through genetic crosses. Unsupervised analysis and differential gene and protein expression were performed to retrieve CNM molecular signatures. Longitudinal studies before, at, and after disease onset highlighted potential disease causes and consequences. Main pathways in the common CNM disease signature include muscle contraction, regeneration and inflammation. The common therapy signature revealed novel potential therapeutic targets, including the calcium regulator sarcolipin. We identified several novel biomarkers validated in muscle and/or plasma through RNA quantification, western blotting, and enzyme-linked immunosorbent assay (ELISA) assays, including ANXA2 and IGFBP2. This study validates the concept of using multi-omics approaches to identify molecular signatures common to different disease forms and therapeutic strategies.
Identifiants
pubmed: 33940157
pii: S1525-0016(21)00247-1
doi: 10.1016/j.ymthe.2021.04.033
pmc: PMC8353243
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Bin1 protein, mouse
0
Nerve Tissue Proteins
0
Oligonucleotides, Antisense
0
Tumor Suppressor Proteins
0
Tamoxifen
094ZI81Y45
Protein Tyrosine Phosphatases, Non-Receptor
EC 3.1.3.48
myotubularin
EC 3.1.3.48
DNM2 protein, human
EC 3.6.5.5
Dynamin II
EC 3.6.5.5
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2514-2534Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.L. is co-founder of Dynacure (Illkirch, France). The remaining authors declare no competing interests.
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