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Early onset of inflammation and later involvement of TGFß 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.

address correspondence and reprint requests to Dr. Yi-Wen Chen, Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010; e-mail: ychen{at}cnmcresearch.org.

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)-ß pathway was strongly induced in symptomatic patients, with expression of TGFß 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 TGFß and failure of metabolic pathways later in the disease.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 27 issue to find the link for this article.

This article was previously published in electronic format as an Expedited E-Pub on August 10, 2005, at www.neurology.org.

Supported by National Institutes of Health Grants 5R21AR048318 (Y.W.C.) and 5R01NS029525-09 (E.P.H), Vernon Lynch Memorial Fellowship in Arthritis Research (K.N.), Arthritis Investigator Award from National Arthritis Foundation (K.N.), Maryland Arthritis Research Centre grant (K.N.), Myositis Association grant (K.N.), Muscular Dystrophy Association Grant MDA3455 (M.B.), and donations from the Crystal Ball, Richmond, VA (M.B.).

Received February 2, 2005. Accepted in final form June 2, 2005.

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