Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle

Abstract

The primary cause of Duchenne muscular dystrophy (DMD) is a mutation in the dystrophin gene leading to the absence of the corresponding RNA transcript and protein. Absence of dystrophin leads to disruption of the dystrophin-associated protein complex and substantial changes in skeletal muscle pathology. Although the histological pathology of dystrophic tissue has been well documented, the underlying molecular pathways remain poorly understood. To examine the pathogenic pathways and identify new or modifying factors involved in muscular dystrophy, expression microarrays were used to compare individual gene expression profiles of skeletal muscle biopsies from 12 DMD patients and 12 unaffected control patients. Two separate statistical analysis methods 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 105 genes that differ significantly in expression level between unaffected and DMD muscle. Many of the differentially expressed genes reflect changes in histological pathology. For instance, immune response signals and extracellular matrix genes are overexpressed in DMD muscle, an indication of the infiltration of inflammatory cells and connective tissue. Significantly more genes are overexpressed than are underexpressed in dystrophic muscle, with dystrophin underexpressed, whereas other genes encoding muscle structure and regeneration processes are overexpressed, reflecting the regenerative nature of the disease.

Partial least squares based identification of Duchenne muscular dystrophy specific genes

“…In addition, increased expressions of genes encoding ECM components, such as fibril-forming collagens (types I and III), were also detected. This is also consistent with previous studies (Haslett et al, 2002;Pescatori et al, 2007), and increased ECM synthesis may contribute to the progressive fibrosis of muscle in DMD patients. Moreover, ECM-receptor interaction (hsa4512) is one of the pathways that are enriched with deregulated genes and all differentially expressed genes in this pathway are upregulated (Fig.…”

“…This may result from the infiltration of immune cells into the muscles (Mcdouall et al, 1990;Spencer et al, 1997;Cai et al, 2000) and also in elevated levels of various inflammatory cytokines. For muscle regeneration, two genes which encode embryonic and perinatal myosin heavy chains (MYH3 and MYH8) were overexpressed, consistent with Haslett et al (2002). MYH8 was the most significantly differentially expressed gene.…”

“…Current available large-scale parallel gene expression analysis has provided greater ease for investigating the underlying molecular pathophysiological mechanisms of DMD. Several gene expression profiling studies (Chen et al, 2000;2005;Haslett et al, 2002;Pescatori et al, 2007;Wong et al, 2009) have been carried out, providing insights into the pathology of DMD. These studies typically implemented standard analysis of variance/regression to identify the differentially expressed genes over two types of samples.…”

Expression profiling reveals altered satellite cell numbers and glycolytic enzyme transcription in nemaline myopathy muscle

“…The resulting data sets define gene expression patterns characteristic of NM skeletal muscle and demonstrate widespread down-regulation of key energy metabolism and muscle differentiation pathways. These patterns are distinct from those of muscles undergoing dystrophic or inflammatory processes (5)(6)(7)(8).…”

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

“…1 Although the molecular cause of the disease is well documented, the secondary signaling pathways that are altered by the lack of a functional dystrophin protein remain understudied. 2,3 Dystrophic muscle is known to undergo cycles of regeneration to form new myofibers as a consequence of myofibers loss and myoblast cell dysregulation. 4 WNT (wingless-type MMTV integration site family) signaling factors are known to regulate both the maintenance of muscle satellite cells (MSCs), and their ability to differentiate into myofibers.…”