Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies

• Published in: Molecular therapy 2021-08, Vol.29 (8), p.2514-2534
• Main Authors: Djeddi, Sarah, Reiss, David, Menuet, Alexia, Freismuth, Sébastien, de Carvalho Neves, Juliana, Djerroud, Sarah, Massana-Muñoz, Xènia, Sosson, Anne-Sophie, Kretz, Christine, Raffelsberger, Wolfgang, Keime, Céline, Dorchies, Olivier M., Thompson, Julie, Laporte, Jocelyn
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Animals; Artificial Intelligence; biomarker; centronuclear myopathy; Computer Science; congenital myopathy; Disease Models, Animal; Dynamin II - antagonists & inhibitors; Gene Expression Profiling - methods; genetic disease; Humans; Longitudinal Studies; Mass Spectrometry; Mice; MTM1; Myopathies, Structural, Congenital - drug therapy; Myopathies, Structural, Congenital - genetics; Myopathies, Structural, Congenital - metabolism; myostatin; myotubular myopathy; myotubularin; Nerve Tissue Proteins - antagonists & inhibitors; Oligonucleotides, Antisense - therapeutic use; omics; Original; Protein Tyrosine Phosphatases, Non-Receptor - genetics; Proteomics - methods; RNA interference; Sequence Analysis, RNA; Tamoxifen - therapeutic use; Tumor Suppressor Proteins - antagonists & inhibitors; XLMTM
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2021.04.033

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. [Display omitted] A multi-omics analysis is performed on transgenic mouse lines faithfully modeling different forms of centronuclear myopathies treated or not with several therapeutic approaches. The common disease and therapy signatures are described at the molecular level. Potential circulating biomarkers are identified and await confirmation in patients.