Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression

Abstract

Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) patients has been used to describe muscle tissue alterations in DMD children older than 5 years. By studying the expression profile of 19 patients younger than 2 years, we describe with high resolution the gene expression signature that characterizes DMD muscle during the initial or "presymptomatic" phase of the disease. We show that in the first 2 years of the disease, DMD muscle is already set to express a distinctive gene expression pattern considerably different from the one expressed by normal, age-matched muscle. This "dystrophic" molecular signature is characterized by a coordinate induction of genes involved in the inflammatory response, extracellular matrix (ECM) remodeling and muscle regeneration, and the reduced transcription of those involved in energy metabolism. Despite the lower degree of muscle dysfunction experienced, our younger patients showed abnormal expression of most of the genes reported as differentially expressed in more advanced stages of the disease. By analyzing our patients as a time series, we provide evidence that some genes, including members of three pathways involved in morphogenetic signaling-Wnt, Notch, and BMP-are progressively induced or repressed in the natural history of DMD.

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.…”

“…Two datasets (GSE6011 and GSE3307), which included 27 DMD patients and 14 healthy controls, were used in subsequent analysis. Dystrophin protein was absent in all patients (Chen et al, 2000;Pescatori et al, 2007). Sample information for all subjects is listed in Table 1.…”

“…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.…”

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

“…The most significant increases were in patients with Duchenne MD (P < 0.0001) and juvenile dermomyositis (P < 0.0001). Furthermore, the literature supports that the increase in periostin mRNA levels in Duchenne MD muscle is agedependent and is elevated most significantly (a twofold increase) in young children (24).…”

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

“…8 In DMD, a similar dysregulation of the transcriptional-level WNT signaling components has been reported. 9 MicroRNAs (miRNAs) have been shown to have an essential role in muscle development, differentiation, and disease. [10][11][12][13][14][15] Previously, we defined a miRNA biosignature of different muscle diseases and revealed dysregulated miRNAs that were either common or unique to each muscle disease.…”