Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice

Abstract

The mdx mouse is a model for human Duchenne muscular dystrophy (DMD), an X-linked degenerative disease of skeletal muscle tissue characterized by the absence of the dystrophin protein. The mdx mice display a much milder phenotype than DMD patients. After the first week of life when all mdx muscles evolve like muscles of young DMD patients, mdx hindlimb muscles substantially compensate for the lack of dystrophin, whereas mdx diaphragm muscle becomes progressively affected by the disease. We used cDNA microarrays to compare the expression profile of 1,082 genes, previously selected by a subtractive method, in control and mdx hindlimb and diaphragm muscles at 12 time points over the first year of the mouse life. We determined that 1) the dystrophin gene defect induced marked expression remodeling of 112 genes encoding proteins implicated in diverse muscle cell functions and 2) two-thirds of the observed transcriptomal anomalies differed between adult mdx hindlimb and diaphragm muscles. Our results showed that neither mdx diaphram muscle nor mdx hindlimb muscles evolve entirely like the human DMD muscles. This finding should be taken under consideration for the interpretation of future experiments using mdx mice as a model for therapeutic assays.

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

“…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.…”

Transcriptional profile of postmortem skeletal muscle

“…Several microarray-based studies of gene expression in normal and diseased states have been performed on human skeletal muscles obtained at biopsy or autopsy (1,8,20,21,33) and on murine skeletal muscle obtained immediately postmortem (30,32,37,40). These studies identified a number of genes in various functional categories that are differentially expressed in the disease states, suggesting that major alterations in tissue have far-reaching consequences for gene expression.…”

Gene expression profiling of diaphragm muscle in α2-laminin (merosin)-deficient dy/dy dystrophic mice

“…However, there were divergences between diaphragm and limb muscle within themes of which specific genes were altered, especially within the inflammatory and muscle-specific gene categories. Rouger et al (38) studied both diaphragm and limb muscle using cDNA microarrays that tested expression of a much more focused group of 1,082 genes. They found some genes with altered expression in both muscle groups, others with altered expression in diaphragm only or limb muscle only, and yet others with altered but different expression in the two muscle groups.…”