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Assessment of disease activity in muscular dystrophies by noninvasive imaging
Katie K. Maguire, … , Sedona Speedy, Thomas A. Rando
Katie K. Maguire, … , Sedona Speedy, Thomas A. Rando
Published April 24, 2013
Citation Information: J Clin Invest. 2013;123(5):2298-2305. https://doi.org/10.1172/JCI68458.
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Technical Advance Article has an altmetric score of 19

Assessment of disease activity in muscular dystrophies by noninvasive imaging

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Abstract

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.

Authors

Katie K. Maguire, Leland Lim, Sedona Speedy, Thomas A. Rando

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Figure 3

Regenerative activity in hind limb muscles of Dysf–/–/Pax7CreER/LuSEAP mice as a function of age.

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Regenerative activity in hind limb muscles of Dysf–/–/Pax7CreER/LuSEAP m...
(A) Hind limb muscles of Dysf–/–/Pax7CreER/LuSEAP mice imaged at 3, 6, 9, and 12 months of age. The luciferase signals increase in the hind limb muscles over time, with more signals emanating from the proximal muscles after 6 months of age. Scale to the right of the image represents photon emission from the tissue surface and is expressed as p/s/cm2/sr (or radiance). (B) Luciferase signals were quantified in proximal or distal hind limb muscles of Dysf–/–/Pax7CreER/LuSEAP mice. **P < 0.05; n = 12. (C) Representative images demonstrating the accrual of luciferase-positive myofibers in quadriceps muscles of Dysf–/–/Pax7CreER/LuSEAP mice at different ages. Scale bar: 50 μm. (D) Quantitation of the percentage of luciferase-positive quadriceps fibers from mice sacrificed at 3, 6, 9, and 12 months of age. *P < 0.05; n ≥ 3; value at each time point compared with that at 3 months of age.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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