Endomysial fibrosis in duchenne muscular dystrophy: A marker of poor outcome associated with macrophage alternative activation

ArticleinJournal of Neuropathology and Experimental Neurology 68(7):762-73 · June 2009with39 Reads
DOI: 10.1097/NEN.0b013e3181aa31c2 · Source: PubMed
There is considerable interindividual variability in motor function among patients with Duchenne muscular dystrophy (DMD); moreover, pathogenetic mechanisms of motor dysfunction in DMD are not understood. Using multiparametric analysis, we correlated initial histologic alterations in quadriceps muscle biopsies from 25 steroid therapy-free patients with DMD with 13 relevant clinical features assessed by a single clinical team during a long-term period (mean, >10 years). There was no residual muscle dystrophin by immunohistochemistry and Western blot analysis in the biopsies. Myofiber size, hypercontracted fibers, necrotic/basophilic fibers, endomysial and perimysial fibrosis, and fatty degeneration were assessed by morphometry. Endomysial fibrosis was the only myopathologic parameter that significantly correlated with poor motor outcome as assessed by quadriceps muscle strength, manual muscle testing of upper and lower limbs at 10 years, and age at ambulation loss (all p<0.002). Motor outcome and fibrosis did not correlate with genotype. Myofibers exhibited oxidative stress-induced protein alterations and became separated from capillaries by fibrosis that was associated with both increase of CD206+ alternatively activated macrophages and a relative decrease of CD56+ satellite cells (both p<0.0001). This study provides a strong rationale for antifibrotic therapeutic strategies in DMD and supports the view that alternatively activated macrophages that are known to inhibit myogenesis while promoting cellular collagen production play a key role in myofibrosis.
    • "This has also been demonstrated as the case for myopathies and dystrophies, where endo-and perimysial fibrosis in the form of accumulated coallagen I, III, IV and fibronectin predominates [106, 107]. In DMD, endomysial fibrosis has been one of the strongest predictors of motor deterioration [31] . Therefore, early identification of loss in muscle strength or mass can be achieved by following closely the extent of fibrosis in the muscle tissue. "
    Article · Aug 2016 · American Journal of Translational Research
    • "Together with evidence of the positive effects of glucocorticoids in patients with DMD, the rationale for pursuing the anti-inflammatory approach in DMD therapy has come into clearer focus. Endomysial fibrosis in the muscles of patients with DMD is correlated with clinical severity and because the transforming growth factor-β (TGF-β) pathway plays an important role in fibrotic tissue formation, this has now become the major target of antifibrotic approaches in DMD [80, 81]. Increases in reactive oxygen species have also been found in DMD, which are considered to contribute to membrane permeability , protein degradation, and inflammatory pathway activation [82], and thus they are potential therapeutic targets. "
    [Show abstract] [Hide abstract] ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative muscle disorder caused by the absence of dystrophin. There is no curative therapy, although innovative therapeutic approaches have been aggressively investigated over recent years. Currently, the international clinical trial registry platform for this disease has been constructed and clinical trials for innovative therapeutic approaches are underway. Among these, exon skipping and read-through of nonsense mutations are in the most advanced stages, with exon skipping theoretically applicable to a larger number of patients. To date, exon skipping that targets exons 51, 44, 45, and 53 is being globally investigated including in USA, EU, and Japan. The latest announcement from Japan was made, demonstrating successful dystrophin production in muscles of patients with DMD after treating with exon 53 skipping antisense oligonucleotides (ASOs). However, the innovative therapeutic approaches have demonstrated limited efficacy. To address this issue in exon skipping, studies to unveil the mechanism underlying gymnotic delivery of ASO uptake in living cells have been conducted in an effort to improve in vivo delivery. Further, establishing the infrastructures to integrate multi-institutional clinical trials are needed to facilitate the development of successful therapies for DMD, which ultimately is applicable to other myopathies and neurodegenerative diseases, including spinal muscular atrophy and motor neuron diseases.
    Full-text · Article · Jun 2016
    • "One of the causes of muscle damage and loss of function is the development of fibrosis, which is characterized by excessive accumulation of extracellular matrix (ECM) that replaces muscle tissue with connective tissue, dramatically affecting the environment of the fibers and normal muscle physiology [4][5][6][7][8][9]. Pathologic features of DMD include myofiber atrophy, fatty degeneration, necrosis and fibrosis, but only fibrosis has been shown through clinical studies to correlate with poor motor outcome, evaluated by muscle strength and age at loss of ambulation [10]. This finding supports the notion that fibrosis directly contributes to progressive muscle dysfunction and the lethal phenotype of DMD [6] . "
    Full-text · Dataset · May 2016 · American Journal of Translational Research
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