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Yokota, T, Lu, QL, Morgan, JE, Davies, KE, Fisher, R, Takeda, S et al.. Expansion of revertant fibers in dystrophic mdx muscles reflects activity of muscle precursor cells and serves as an index of muscle regeneration. J Cell Sci 119(Pt 13): 2679-2687

University of Oxford, Oxford, England, United Kingdom
Journal of Cell Science (Impact Factor: 5.33). 08/2006; 119(Pt 13):2679-87. DOI: 10.1242/jcs.03000
Source: PubMed

ABSTRACT Duchenne muscular dystrophy and the mdx mouse myopathies reflect a lack of dystrophin in muscles. However, both contain sporadic clusters of revertant fibers (RFs) that express dystrophin. RF clusters expand in size with age in mdx mice. To test the hypothesis that the expansion of clusters is achieved through the process of muscle degeneration and regeneration, we analyzed muscles of mdx mice in which degeneration and regeneration were inhibited by the expression of micro-dystrophins or utrophin transgenes. Postnatal RF expansion was diminished in direct correlation to the protective effect of the transgene expression. Similarly, expansion of RFs was inhibited when muscle regeneration was blocked by irradiation. However, in irradiated muscles, irradiation-tolerant quiescent muscle precursor cells reactivated by notexin effectively restored RF expansion. Our observations demonstrate that revertant events occur initially within a subset of muscle precursor cells. The proliferation of these cells, as part of the regeneration process, leads to the expansion of RF clusters within degenerating muscles. This expansion of revertant clusters depicts the cumulative history of regeneration, thus providing a useful index for functional evaluation of therapies that counteract muscle degeneration.

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Available from: Kay E Davies, Mar 17, 2014
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    • "Surprisingly, very few X-gal +ve nuclei were detected in muscles grafted with mdx satellite cells (4.5 ± 1.6 myofibers with at least one X-gal +ve nucleus), indicating significantly less donor-derived myofibers (P b 0.05) than those obtained from donor wild-type 3F-nlacZ-2E satellite cells (84 ± 33 myofibers with at least one X-gal +ve nucleus and 223 ± 100 dystrophin + ve myofibers) (Fig. 1A–E). It should be noted that the rare, dystrophin +ve, X-gal -ve myofibers (Fig. 2B) in these muscles grafted with donor cells derived from mdx mice are most likely host, revertant myofibers (Hoffman et al, 1990; Lu et al, 2000; Yokota et al, 2006). To test the validity of the donor 3F-nlacZ-2E transgene as a marker of muscle in mdx, mdx × 3F-nlacZ-2E isolated EDL myofibers of donor muscles were incubated in X-gal to reveal β-galactosidase activity. "
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    ABSTRACT: Grafted mdx satellite cells regenerate muscle as well as wild-type satellite cells•Aged mdx myofibers bear more satellite cells than aged wild type fibers.•mdx satellite cells retain their ability to activate•Aged mdx satellite cells are robustly regenerative in vivo
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    • "The literature suggests that " cycles " of muscle degeneration and regeneration contribute to progressive muscle wasting [18] [19] [20] which is likely antagonized further by the immune response [8] [9] [10] [11] [12]. This relationship suggests a predator-prey-like interaction between the immune system and the tissue, which has been reported in many other diseases [21]. "
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.
    BioMed Research International 06/2014; 2014:871810. DOI:10.1155/2014/871810 · 2.71 Impact Factor
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    • "evocably damaged by the same protocol , with a breakdown in [ Ca 2+ ] i homeostasis . Since dystrophin is absent in both branched and unbranched mdx fibres , it can be concluded that branching itself plays a significant role in the increased susceptibility to damage . A small number of branched fibres may also be revertant and contain dystrophin ( Yokota et al . 2006 ) . The FDB study demonstrates that in isolated fibres with the connective tissue support removed , the branch points cannot even sustain the unloaded isotonic contractions that do not damage non - branched dystrophin - deficient mdx fibres ."
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    ABSTRACT: In the dystrophinopathies, skeletal muscle fibres undergo cycles of degeneration and regeneration, with regenerated fibres displaying a branched morphology. This study tests the hypothesis that regenerated branched fibres are mechanically weakened by the presence of branches and are damaged by contractions which do not affect unbranched dystrophin-negative fibres. Experiments were carried out on single fast-twitch fibres and whole muscle from the dystrophin-negative mdx mouse. Fura-2 was ionophoresed into fibres to measure intracellular Ca(2+) concentration ([Ca(2+)](i)). Single branched mdx fibres have abnormal Ca(2+) kinetics, with the [Ca(2+)](i) transient at the peak of the twitch depressed, are damaged by fatiguing activation, resulting in a breakdown of Ca(2+) homeostasis, and break at branch points when submaximally activated in skinned fibre experiments. When old intact isolated mdx muscles, with >90% branched fibres, are eccentrically activated with a moderate eccentric protocol there is a 40 +/- 8% reduction in maximal force. Isolated single fibres from these muscles show areas of damage at fibre branch points. This same eccentric protocol causes no force loss in either littermate control muscles or mdx muscles with <10% branched fibres. I present a two-stage hypothesis for muscle damage in the dystrophinopathies, as follows: stage 1, the absence of dystrophin disrupts ion channel function, causing an activation of necrotizing Ca(2+)-activated proteases, which results in regenerated branched fibres; and stage 2, branched fibres are mechanically damaged during contraction. These results may have implications when considering therapies for boys with Duchenne muscular dystrophy. In particular, any therapy aimed at rescuing the defective gene will presumably have to do so before the number of branched fibres has increased to a level where the muscle is mechanically compromised.
    Experimental physiology 02/2010; 95(5):641-56. DOI:10.1113/expphysiol.2009.052019 · 2.87 Impact Factor
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