Gene expression profiling of Duchenne muscular dystrophy skeletal muscle

Abstract

The primary cause of Duchenne muscular dystrophy (DMD) is a mutation in the dystrophin gene, leading to absence of the corresponding protein, disruption of the dystrophin-associated protein complex, and substantial changes in skeletal muscle pathology. Although the primary defect is known and the histological pathology well documented, the underlying molecular pathways remain in question. To clarify these pathways, we used expression microarrays to compare individual gene expression profiles for skeletal muscle biopsies from DMD patients and unaffected controls. We have previously published expression data for the 12,500 known genes and full-length expressed sequence tags (ESTs) on the Affymetrix HG-U95Av2 chips. Here we present comparative expression analysis of the 50,000 EST clusters represented on the remainder of the Affymetrix HG-U95 set. Individual expression profiles were generated for biopsies from 10 DMD patients and 10 unaffected control patients. Two methods of statistical analysis were used to interpret the resulting data (t-test analysis to determine the statistical significance of differential expression and geometric fold change analysis to determine the extent of differential expression). These analyses identified 183 probe sets (59 of which represent known genes) that differ significantly in expression level between unaffected and disease muscle. This study adds to our knowledge of the molecular pathways that are altered in the dystrophic state. In particular, it suggests that signaling pathways might be substantially involved in the disease process. It also highlights a large number of unknown genes whose expression is altered and whose identity therefore becomes important in understanding the pathogenesis of muscular dystrophy.

Inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ signaling mediates delayed myogenesis in Duchenne muscular dystrophy fetal muscle

“…The lack of dystrophin and the consequent disorganization of the membraneassociated cytoskeleton could induce a dysfunction of calcium influxes and releases, with cumulative consequences on fetal DMD myogenesis, and adult muscle damage. However, dystrophin absence might be more crucial, and might not simply unbalance the mechanical structure of plasma membrane but deeply modify gene expression, as suggested by previously published transcriptomic analysis of dystrophic muscles (Haslett et al, 2003;Ghahramani Seno et al, 2010).…”

The satellite cell as a companion in skeletal muscle plasticity:currency, conveyance, clue, connector and colander

“…Other experiments have profiled gene expression against hierarchies of genes (Boer et al, 2002;Fluck et al, 2005;Haslett et al, 2003;Nikawa et al, 2004;Porter et al, 2004;Seale et al, 2004a;Wu et al, 2003). Since the viability of the stem cells in their stem-like capacity is observed to decline after tissue dissociation and flow cytometry, fatemapping experiments in other tissues have enabled investigators to follow the migration and multi-lineage differentiation of particular single cells [e.g.…”

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.…”