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      Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy

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          Abstract

          In Duchenne muscular dystrophy, asynchronous regeneration in microenvironments within muscle tissue results in development of fibrosis in lieu of global muscle recovery.

          Abstract

          We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor β–centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues.

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          Multiple-laboratory comparison of microarray platforms.

          Rafael A. Irizarry, Daniel P Warren, Forrest Spencer … (2005)
          Microarray technology is a powerful tool for measuring RNA expression for thousands of genes at once. Various studies have been published comparing competing platforms with mixed results: some find agreement, others do not. As the number of researchers starting to use microarrays and the number of cross-platform meta-analysis studies rapidly increases, appropriate platform assessments become more important. Here we present results from a comparison study that offers important improvements over those previously described in the literature. In particular, we noticed that none of the previously published papers consider differences between labs. For this study, a consortium of ten laboratories from the Washington, DC-Baltimore, USA, area was formed to compare data obtained from three widely used platforms using identical RNA samples. We used appropriate statistical analysis to demonstrate that there are relatively large differences in data obtained in labs using the same platform, but that the results from the best-performing labs agree rather well.
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            Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy.

            James G. Tidball, Bo Deng, Vy X Nguyen … (2009)
            Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood. Previous investigations have shown that muscle macrophages may play an important role in promoting the pathology in the mdx mouse model of DMD. In the present study, we investigate the mechanism through which macrophages promote mdx dystrophy and assess whether the phenotype of the macrophages changes between the stage of peak muscle necrosis (4 weeks of age) and muscle regeneration (12 weeks). We find that 4-week-old mdx muscles contain a population of pro-inflammatory, classically activated M1 macrophages that lyse muscle in vitro by NO-mediated mechanisms. Genetic ablation of the iNOS gene in mdx mice also significantly reduces muscle membrane lysis in 4-week-old mdx mice in vivo. However, 4-week mdx muscles also contain a population of alternatively activated, M2a macrophages that express arginase. In vitro assays show that M2a macrophages reduce lysis of muscle cells by M1 macrophages through the competition of arginase in M2a cells with iNOS in M1 cells for their common, enzymatic substrate, arginine. During the transition from the acute peak of mdx pathology to the regenerative stage, expression of IL-4 and IL-10 increases, either of which can deactivate the M1 phenotype and promote activation of a CD163+, M2c phenotype that can increase tissue repair. Our findings further show that IL-10 stimulation of macrophages activates their ability to promote satellite cell proliferation. Deactivation of the M1 phenotype is also associated with a reduced expression of iNOS, IL-6, MCP-1 and IP-10. Thus, these results show that distinct subpopulations of macrophages can promote muscle injury or repair in muscular dystrophy, and that therapeutic interventions that affect the balance between M1 and M2 macrophage populations may influence the course of muscular dystrophy.
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              Early onset of inflammation and later involvement of TGFbeta in Duchenne muscular dystrophy.

              R Shi, Eric Hoffman, Julie Y. Chen … (2005)
              To identify stage-specific induction of molecular pathology pathways in Duchenne muscular dystrophy (DMD). 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. Activated tissue dendritic cells, expression of toll-like receptor 7, and strong induction of nuclear factor-kappaB 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)-beta pathway was strongly induced in symptomatic patients, with expression of TGFbeta type II receptor and apoptosis signal-regulating kinase 1 proteins on subsets of mature DMD myofibers. Our data show stage-specific remodeling of human dystrophin-deficient muscle, with inflammatory pathways predominating in the presymptomatic stages and acute activation of TGFbeta and failure of metabolic pathways later in the disease.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Biol
                Journal ID (iso-abbrev): J. Cell Biol
                Journal ID (hwp): jcb
                Journal ID (publisher-id): jcb
                Title: The Journal of Cell Biology
                Publisher: The Rockefeller University Press
                ISSN (Print): 0021-9525
                ISSN (Electronic): 1540-8140
                Publication date (Print): 13 October 2014
                Volume: 207
                Issue: 1
                Pages: 139-158
                Affiliations
                [1 ]Center for Genetic Medicine Research, Children’s National Medical Center , and [2 ]Department of Integrative Systems Biology, George Washington University, Washington, DC 20010
                [3 ]The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 24061
                Author notes
                Correspondence to Eric P. Hoffman: ehoffman@ 123456childrensnational.org

                S. Dadgar, Z. Wang, and H. Johnston contributed equally to this paper.

                Article
                Publisher ID: 201402079
                DOI: 10.1083/jcb.201402079
                PMC ID: 4195829
                PubMed ID: 25313409
                SO-VID: 52a4b4f6-51aa-400e-a8ca-3944945cef27
                Copyright © © 2014 Dadgar et al.
                License:

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                Date received : 17 February 2014
                Date accepted : 29 August 2014
                Categories
                Subject: Research Articles
                Subject: Article

                ScienceOpen disciplines: Cell biology
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                ScienceOpen disciplines: Cell biology

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