A proton nuclear magnetic resonance study of muscle growth, dystrophy, repair and drug treatments in control and mdx mice

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McIntosh, Laura Maureen
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Proton nuclear magnetic resonance spectroscopy (1-H NMR) can be used to study skeletal muscle metabolism. The mdx mouse is a unique animal which allows study of muscle regeneration, and models the disease of Duchenne muscular dystrophy (DMD). The goals of these studies were to determine the potential of 1-H NMR spectroscopy as an alternative to conventional histology in monitoring: (1) the progression of mdx dystrophy, and (2) beneficial treatments (glucocorticoids) on mdx dystrophy. In vitro 1-H NMR spectra (ex vivo and perchloric acid extracts) of limb and diaphragm muscles were obtained from different ages of control and mdx mice, and from mice which were treated with prednisone or deflazacort. Peaks with contributions from creatine, taurine and lipids were examined in the ex vivo samples. Additionally, valine, lactate, alanine, glutamate, succinate, glutamine, carnitine, glycine and glucose peaks were examined in spectra from extracts. Decreased levels of taurine and carnitine characterized pre- and active dystrophy intervals in mdx muscle compared to control. Levels of taurine increased with stabilization of the disease with repair. Measures of accumulated muscle repair and many spectral peaks were highly and significantly correlated. Increased amounts of lipids were found in the diaphragm compared to limb spectra. Treatment, which improved muscle phenotype, resulted in increased levels of taurine. Also, glutamate, alanine and succinate were decreased in mdx diaphragm compared to control, and increased with deflazacort-treatment in mdx DIA. Therefore, 1-H NMR differentially discriminates: (1) control and mdx muscle, (2) the progression of mdx dystrophy and developmental stages in normal growth, (3) mild and severe dystrophic phenotypes (diaphragm vs. limb), and (4) changes associated with improved muscle phenotype and regeneration (due to treatment or injury). The results focus on monitoring muscle repair, not degeneration. Preliminary magnetic resonance imaging studies point to eventual application of the findings to non-invasive measurement of treatment effects by in vivo 1-H NMR spectroscopy. We conclude that 1-H NMR is a reliable tool in the objective investigation of muscle repair status during muscular dystrophy.