Article

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: 5.43). 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
    Full-text · Article · Nov 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). "
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    ABSTRACT: Duchenne muscular dystrophy is an inherited disorder that is characterized by progressive skeletal muscle weakness and wasting, with a failure of muscle maintenance/repair mediated by satellite cells (muscle stem cells). The function of skeletal muscle stem cells resident in dystrophic muscle may be perturbed by being in an increasing pathogenic environment, coupled with constant demands for repairing muscle. To investigate the contribution of satellite cell exhaustion to this process, we tested the functionality of satellite cells isolated from the mdx mouse model of Duchenne muscular dystrophy. We found that satellite cells derived from young mdx mice contributed efficiently to muscle regeneration within our in vivo mouse model. To then test the effects of long-term residence in a dystrophic environment, satellite cells were isolated from aged mdx muscle. Surprisingly, they were as functional as those derived from young or aged wild type donors. Removing satellite cells from a dystrophic milieu reveals that their regenerative capacity remains both intact and similar to satellite cells derived from healthy muscle, indicating that the host environment is critical for controlling satellite cell function. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Nov 2014 · Stem Cell Research
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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.
    Full-text · Article · Jun 2014 · BioMed Research International
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