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

Mol Ther. 2021 Aug 4;29(8):2514-2534. doi: 10.1016/j.ymthe.2021.04.033. Epub 2021 May 1.


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.

Keywords: MTM1; RNA interference; XLMTM; biomarker; centronuclear myopathy; congenital myopathy; genetic disease; myostatin; myotubular myopathy; myotubularin; omics.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Myopathies, Structural, Congenital / genetics
  • Myopathies, Structural, Congenital / metabolism
  • 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


  • Adaptor Proteins, Signal Transducing
  • Bin1 protein, mouse
  • Nerve Tissue Proteins
  • Oligonucleotides, Antisense
  • Tumor Suppressor Proteins
  • Tamoxifen
  • Protein Tyrosine Phosphatases, Non-Receptor
  • myotubularin
  • DNM2 protein, human
  • Dynamin II