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in Duchenne muscular dystrophy
From the Research Center for Genetic Medicine (Drs. Chen, Bakay, Shi, and Hoffman and O. McIntyre), Children’s National Medical Center, George Washington University, Washington, DC; and the Division of Rheumatology (Drs. Nagaraju and Rawat), Department of Medicine, Johns Hopkins University, Baltimore, MD.
* To whom correspondence should be addressed. E-mail: ychen{at}cnmcresearch.org.
Abstract-- Objective: To identify stage-specific induction of molecular pathology pathways in Duchenne muscular dystrophy (DMD). Methods: We performed mRNA profiling using muscles from fetopsies, infants (aged 8 to 10 months), and symptomatic patients (aged 5 to 12 years) with DMD, and age- and sex-matched controls. We performed immunohistochemistry to determine changes at the protein level and protein localization. Results: Activated tissue dendritic cells, expression of toll-like receptor 7, and strong induction of nuclear factor-
B pathways occurred soon after birth in DMD muscle. Two muscle wasting pathways, atrogin-1 and myostatin, were not induced at any stage of the disease. Normal muscle showed accumulation of glycolytic and oxidative metabolism capacity with increased age, but this accumulation failed in DMD. The transforming growth factor (TGF)-
pathway was strongly induced in symptomatic patients, with expression of TGF type II receptor and apoptosis signal-regulating kinase 1 proteins on subsets of mature DMD myofibers Conclusions: Our data show stage-specific remodeling of human dystrophin-deficient muscle, with inflammatory pathways predominating in the presymptomatic stages and acute activation of TGF and failure of metabolic pathways later in the disease.
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