Muscle genome-wide expression profiling during disease evolution in mdx mice

Abstract

Mdx mice show a milder phenotype than Duchenne patients despite bearing an analogous genetic defect. Our aim was to sort out genes, differentially expressed during the evolution of skeletal muscle mdx mouse disease, to elucidate the mechanisms by which these animals overcome the lack of dystrophin. Genome-wide microarray-based gene expression analysis was carried out at 3 wk and 1.5 and 3 mo of life. Candidate genes were selected by comparing: 1) mdx vs. controls at each point in time, and 2) mdx mice and 3) control mice among the three points in time. The first analysis showed a strong upregulation (96%) of inflammation-related genes and in >75% of genes related to cell adhesion, muscle structure/regeneration, and extracellular matrix remodeling during mdx disease evolution. Lgals3, Postn, Ctss, and Sln genes showed the strongest variations. The analysis performed among points in time demonstrated significant changes in Ecm1, Spon1, Thbs1, Csrp3, Myo10, Pde4b, and Adamts-5 exclusively during mdx mice lifespan. RT-PCR analysis of Postn, Sln, Ctss, Thbs1, Ecm1, and Adamts-5 expression from 3 wk to 9 mo, confirmed microarray data and demonstrated variations beyond 3 mo of age. A high-confidence functional network analysis demonstrated a strong relationship between them and showed two main subnetworks, having Dmd-Utrn-Myo10 and Adamts5-Thbs1-Spon1-Postn as principal nodes, which are functionally linked to Abca1, Actn4, Crebbp, Csrp3, Lama1, Lama3, Mical2, Mical3, Myf6, Pxn, and Sparc genes. Candidate genes may participate in the decline of muscle necrosis in mdx mice and could be considered potential therapeutic targets for Duchenne patients.

Comparative transcriptome analysis of muscular dystrophy models Largemyd, Dmdmdx/Largemyd and Dmdmdx: what makes them different?

“…This could indicate an apparent response mechanism to reinforce the links between the ECM and the cytoskeleton, protecting the muscular fibers against contraction damages. 20 A higher expression of Gpnmb (osteoactivin) in dystrophic mice 35 and DMD patients 36 was previously described. Osteoactivin is implicated in the differentiation and function of many cell types.…”

“…Several transcriptome studies in Dmd mdx mouse were published in the last years, [12][13][14][15][16][17][18][19][20] but no studies in Large myd − / − nor in Dmd mdx /Large myd − / − were performed. 9 In Dmd mdx , similar data to the observed in our study were described by Boer et al 14 and Porter et al 17,21 Using an Affymetrix chip of about 12 000 genes/EST, Boer et al 14 identified 58 DEGs in Dmd mdx limb muscles, from which 49 were unregulated while only 9 were downregulated.…”

“…The expression profiling of medial gastrocnemius of Dmd mdx mice revealed that most induced genes belongs to immune response and inflammation. 20 Porter et al 16 found 242 DEGs in the Dmd mdx gastrocnemius, of which 29.8% were classified as inflammatory genes, determining a chronic inflammatory response. Similar results were reported also by other authors.…”

Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice

“…Such studies led us to examine proteases that are both induced in dystrophic skeletal muscle and amenable to pharmacologic inhibition, which might represent a new therapeutic approach in DMD. One of these proteases, Ctss, was previously identified as an mRNA species up-regulated in both muscle from DMD patients and mdx mice, although the functional effects of this increase were not investigated (17)(18)(19).…”

Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway

“…It contains four fasciclin domains that are also observed in the insect protein fasciclin I, which is involved in neuronal cell-cell adhesion (11,12). Periostin expression is low at baseline in many adult tissues, but is strongly induced and secreted into the ECM after acute injury, as well as in dystrophic skeletal muscle (13). Periostin is expressed exclusively by fibroblasts or cells that adopt a fibroblast-like phenotype after an injurious event (14).…”