Multiomics Analysis of the mdx/mTR Mouse Model of Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by extensive muscle weakness. Patients with DMD lack a functional dystrophin protein, which transmits force and organizes the cytoskeleton of skeletal muscle. Multiomic studies evaluate combined changes in the transcriptome, proteome, and metabolome, and have been proposed as a way to obtain novel insight about disease processes from preclinical models.We therefore sought to use this approach to study pathological changes in dystrophic muscles.We evaluated hindlimb muscles of male mdx/mTR mice, which lack a functional dystrophin protein and have deficits in satellite cell abundance and proliferative capacity. Wild type (WT) C57BL/6J mice served as controls. Muscle fiber contractility was measured, along with changes in the transcriptome using RNA sequencing, and in the proteome, metabolome, and lipidome using mass spectroscopy. While mdx/mTR mice displayed gross pathological changes and continued cycles of degeneration and regeneration, we found no differences in fiber contractility between strains. However, there were numerous changes in the transcriptome and proteome related to protein balance, contractile elements, extracellular matrix, and metabolism. There was only a 53% agreement in fold change data between the proteome and transcriptome, highlighting the need to study protein abundance along with gene expression measures. Numerous changes in markers of skeletal muscle metabolism were observed, with dystrophic muscles exhibiting elevated glycolytic metabolites. These findings highlight the utility of multiomics in studying muscle disease, and provide additional insight into the pathological changes in dystrophic muscles that might help to guide evidence-based exercise prescription in DMD patients.

Degenerative and regenerative pathways underlying Duchenne muscular dystrophy revealed by single-nucleus RNA sequencing

“…We compared the transcriptomic analyses of ΔEx51 muscle with the mdx/mTR muscle published previously (18) and observed overlap between differentially expressed genes between these two models (SI Appendix, Fig. S2 C and D).…”

Molecular Phenotyping of White Striping and Wooden Breast Myopathies in Chicken

“…Its expression was not altered by the presence of the defects, which is not in favor of a potential role in their establishment. However, recent results showed that adiponectin content may change following posttranscriptional regulation (Van Pelt et al, 2020).…”

Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

“…Besides systematic transcriptomic surveys [190,306] and metabolomic research [60,178,345] in the field of dystrophinopathy, a major area of omics-based biomarker discovery employs mass spectrometric and proteomic screening protocols for the large-scale identification of new peptides, protein fragments and protein biomarker candidates [42,82]. A few studies have also used multi-omics approaches for studying dystrophic changes at the various levels of biological organisation from gene to mRNA to protein expression [122,224,352]. The integration of genomics and proteomics for the in-depth proteogenomic characterisation of rare neuromuscular disorders is an attractive approach that combines advanced proteomic screening with gene discovery [279].…”