Assessment of disease activity in muscular dystrophies by noninvasive imaging

The Journal of clinical investigation (Impact Factor: 13.22). 04/2013; 123(5). DOI: 10.1172/JCI68458
Source: PubMed


Muscular dystrophies are a class of disorders that cause progressive muscle wasting. A major hurdle for discovering treatments for the muscular dystrophies is a lack of reliable assays to monitor disease progression in animal models. We have developed a novel mouse model to assess disease activity noninvasively in mice with muscular dystrophies. These mice express an inducible luciferase reporter gene in muscle stem cells. In dystrophic mice, muscle stem cells activate and proliferate in response to muscle degeneration, resulting in an increase in the level of luciferase expression, which can be monitored by noninvasive, bioluminescence imaging. We applied this noninvasive imaging to assess disease activity in a mouse model of the human disease limb girdle muscular dystrophy 2B (LGMD2B), caused by a mutation in the dysferlin gene. We monitored the natural history and disease progression in these dysferlin-deficient mice up to 18 months of age and were able to detect disease activity prior to the appearance of any overt disease manifestation by histopathological analyses. Disease activity was reflected by changes in luciferase activity over time, and disease burden was reflected by cumulative luciferase activity, which paralleled disease progression as determined by histopathological analysis. The ability to monitor disease activity noninvasively in mouse models of muscular dystrophy will be invaluable for the assessment of disease progression and the effectiveness of therapeutic interventions.

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    • "Whole animal imaging of bioluminescent reporters is a sensitive, quantitative and powerful tool for noninvasively following biological processes in vivo [11], [12]. A host of preclinical animal models have taken advantage of this imaging modality to generate important insights into disease and basic biological mechanisms [13], [14]. However, this technology has not yet been successfully applied to a transgenic animal model that is universally reflective of skeletal muscle atrophy. "
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    • "Although this resource has enhanced the study of transplanted fluorescent cells in vivo, detection in these semitransparent animals is semi-quantitative, can show a low signal-tonoise ratio, and is mainly limited to the labeled cells that are close to the body surface. Luciferase-based imaging has been widely used in mice for monitoring gene expression, cell proliferation and migration, and bacterial and viral infections (Contag and Bachmann, 2002; Luker and Luker, 2008; Liu et al., 2011; Tinkum et al., 2011; Martínez- Corral et al., 2012; Maguire et al., 2013). Detection of bioluminescent signals generated from the luciferase-luciferin reaction is sensitive, virtually free of background noise, and can reveal biological information even from deep tissues. "
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    ABSTRACT: Muscular dystrophies are characterized by progressive muscle weakness and wasting. Among the key obstacles to the development of therapies is the absence of an assay to monitor disease progression in live animals. In this issue of the JCI, Maguire and colleagues use noninvasive bioluminescence imaging to monitor luciferase activity in mice expressing an inducible luciferase reporter gene in satellite cells. These cells proliferate in response to degeneration, therefore increasing the level of luciferase expression in dystrophic muscle.
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