Abstract
In Duchenne muscular dystrophy (DMD), a genetic disruption of dystrophin protein expression results in repeated muscle injury and chronic inflammation. Magnetic resonance imaging shows promise as a surrogate outcome measure in both DMD and rehabilitation medicine that is capable of predicting clinical benefit years in advance of functional outcome measures. The mdx mouse reproduces the dystrophin deficiency that causes DMD and is routinely used for preclinical drug testing. There is a need to develop sensitive, non-invasive outcome measures in the mdx model that can be readily translatable to human clinical trials. Here we report the use of magnetic resonance imaging and spectroscopy techniques for the non-invasive monitoring of muscle damage in mdx mice. Using these techniques, we studied dystrophic mdx muscle in mice from 6 to 12 weeks of age, examining both the peak disease phase and natural recovery phase of the mdx disease course. T2 and fat-suppressed imaging revealed significant levels of tissue with elevated signal intensity in mdx hindlimb muscles at all ages; spectroscopy revealed a significant deficiency of energy metabolites in 6-week-old mdx mice. As the mdx mice progressed from the peak disease stage to the recovery stage of disease, each of these phenotypes was either eliminated or reduced, and the cross-sectional area of the mdx muscle was significantly increased when compared to that of wild-type mice. Histology indicates that hyper-intense MRI foci correspond to areas of dystrophic lesions containing inflammation as well as regenerating, degenerating and hypertrophied myofibers. Statistical sample size calculations provide several robust measures with the ability to detect intervention effects using small numbers of animals. These data establish a framework for further imaging or preclinical studies, and they support the development of MRI as a sensitive, non-invasive outcome measure for muscular dystrophy.
Highlights
Duchenne muscular dystrophy (DMD) is the most common lethal genetic muscle disease diagnosed in children
nuclear magnetic resonance (NMR) spectroscopy shows mdx energetics deficit To determine the state of energy metabolites in mdx versus healthy mice, we assayed the relative levels of phosphate metabolites in mice using un-localized 31P spectroscopy
These findings indicate that at 6 weeks of age, during the peak stage of mdx weakness and necrosis [20,22,23], the mdx mice experience an energy metabolism deficiency that subsequently improves during the recovery phase
Summary
Duchenne muscular dystrophy (DMD) is the most common lethal genetic muscle disease diagnosed in children. Dystrophindeficient mdx mice are a naturally occurring genetic model of DMD and are widely used for preclinical drug testing. Both DMD and mdx muscle undergo cycles of degeneration and regeneration, resulting in a chronic inflammatory state in skeletal muscle. A clearly defined genetic cause and animal models establish a logical path for developing therapies for DMD through translational medicine. Several such compounds have begun to enter clinical trials, including drug classes that target either the skipping of problematic exons [1,2,3] or inflammation and membrane stability [4]. Most outcome measures used are unique to mice or must be substantially altered or interpreted to account for species differences
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