Magnetic Resonance Monitoring of Disease Progression in mdx Mice on Different Genetic Backgrounds

Abstract

Genetic modifiers alter disease progression in both preclinical models and subjects with Duchenne muscular dystrophy (DMD). Using multiparametric magnetic resonance (MR) techniques, we compared the skeletal and cardiac muscles of two different dystrophic mouse models of DMD, which are on different genetic backgrounds, the C57BL/10ScSn-Dmdmdx (B10-mdx) and D2.B10-Dmdmdx (D2-mdx). The proton transverse relaxation constant (T) using both MR imaging and spectroscopy revealed significant age-related differences in dystrophic skeletal and cardiac muscles as compared with their age-matched controls. D2-mdx muscles demonstrated an earlier and accelerated decrease in muscle T compared with age-matched B10-mdx muscles. Diffusion-weighted MR imaging indicated differences in the underlying muscle structure between the mouse strains. The fractional anisotropy, mean diffusion, and radial diffusion of water varied significantly between the two dystrophic strains. Muscle structural differences were confirmed by histological analyses of the gastrocnemius, revealing a decreased muscle fiber size and increased fibrosis in skeletal muscle fibers of D2-mdx mice compared with B10-mdx and control. Cardiac involvement was also detected in D2-mdx myocardium based on both decreased function and myocardial T. These data indicate that MR parameters may be used as sensitive biomarkers to detect fibrotic tissue deposition and fiber atrophy in dystrophic strains.

Using a State-of-the-Art Toolbox to Evaluate Molecular and Functional Readouts of Antisense Oligonucleotide-Induced Exon Skipping in mdx Mice

“…To further confirm that M23D treatment improved muscle quality, 10 randomly selected mdx mice from each group were subjected to volumetric MRI and absolute T2 mapping of gastrocnemius at baseline (5 weeks of age) and at 15 weeks of age. While no differences in gastrocnemius volume were observed with MRI at baseline or at 15 weeks in any of the M23D treatment groups compared to the scrambled control (data not shown), differences were revealed with the quantitative T2-MRI mapping of gastrocnemius muscle by visualizing edemic damage as areas of hyperintensity [33] 2017).…”

Micro-utrophin Improves Cardiac and Skeletal Muscle Function of Severely Affected D2/mdx Mice

“…We demonstrated that 21-week-old D2/ mdx mice exhibit a functionally significant hypertrophic cardiac phenotype compared to age-matched control mice. Due to the variation reported in the cardiac phenotype of D2/ mdx mice, 35 , 36 , 41 we conducted an extensive characterization of the model using cardiac cine-MRI. Cardiac cine-MRI was used, as it is far more accurate than other non-invasive techniques used for assessing cardiac function, such as echocardiogram.…”

“… 35 and Vohra et al. 36 showed that pathology in D2/ mdx mice was more severe than age-matched BL10/ mdx mice. Importantly, left ventricle (LV) systolic dysfunction has been shown in 6-month-old D2/ mdx mice, whereas the equivalent cardiac defects are not present in BL10/ mdx mice until 12 months of age.…”

“Of Mice and Measures”: A Project to Improve How We Advance Duchenne Muscular Dystrophy Therapies to the Clinic

“…The reason for this improvement in D2/ mdx mice needs to be further elucidated, possibly heart wall thickness plays a role. Cardiac magnetic resonance (CMR) imaging was also used in the cardiac assessment of D2/ mdx mice and demonstrated decreased function at 28 weeks of age [ 19 ]. Based on these measures, a mild cardiomyopathy occurs earlier in the D2/ mdx compared to Bl10/ mdx mice.…”

“…In summary, histological and biochemical assessments of fibrosis are recommended, but best methods need to be chosen. If possible, fibrosis quantification should be aligned with biomarkers or CMR of cardiac function or measurements of myocardial composition [ 19 ].…”