Abstract
Duchenne muscular dystrophy (DMD) is an X-linked, lethal muscle degenerative disease caused by loss of dystrophin protein. DMD has no cure and few treatment options. Preclinical efforts to identify potential DMD therapeutics have been hampered by lack of a small animal model that recapitulates key features of the human disease. While the dystrophin-deficient mdx mouse on the C57BL/10 genetic background (B10.mdx) is mildly affected, a more severe muscle disease is observed when the mdx mutation is crossed onto the DBA/2J genetic background (D2.mdx). In this study, the functional and histological progression of the D2.mdx skeletal muscle pathology was evaluated to determine the distinguishing features of disease. Data herein details the muscular weakness and wasting exhibited by D2.mdx skeletal muscle, as well as severe histopathological features, which include the rapid progression of fibrosis and calcifications in the diaphragm and progressive fibrosis accumulation in limb muscles. Furthermore, a timeline of D2.mdx progression is provided that details distinct stages of disease progression. These data support the D2.mdx as a superior small animal model for DMD, as compared to the B10.mdx model. The insights provided in this report should facilitate the design of preclinical evaluations for potential DMD therapeutics.
Highlights
C57BL/10 DBA/2JGenotype Age n Diaphragm SPo (N/cm2) extensor digitorum longus (EDL) Po EDL SPo (N/cm2)378.37 ± 8.44 454.29 ± 17.58† 11 10.76 ± 0.46#10 10.98 ± 0.55 mdx 22 7.09 ± 0.53†459.70 ± 13.30† 420.18 ± 29.70 10 8.08 ± 0.37#342.07 ± 16.68 366.16 ± 12.13*24.43 ± 0.73 30.74 ± 0.69*,†
Emerging interest in utilizing the D2.mdx mouse as a preclinical Duchenne muscular dystrophy (DMD) model for both academic and industry purposes led us to perform a thorough characterization of the ex vivo muscle function exhibited by this line
Because there is no cure for this disease, efforts are underway to identify potential therapeutics to slow the disease progression or transform DMD into a milder form of the disease, Becker muscular dystrophy [ BMD17,18]
Summary
Genotype Age (mo) n Diaphragm SPo (N/cm2) EDL Po (mN) EDL SPo (N/cm). 10 10.98 ± 0.55 mdx 22 7.09 ± 0.53†. Bwt (g) 28.93 ± 1.16 32.28 ± 0.91 33.75 ± 0.87# 31.74 ± 1.04 30.03 ± 1.13 32.66 ± 0.46 26.62 ± 0.61 38.67 ± 1.37*,† 24.49 ± 0.54* 26.36 ± 0.72* 27.06 ± 0.71 24.66 ± 0.74*,#. Tibialis Anterior (mg) 46.16 ± 0.90 59.18 ± 1.65† 77.62 ± 1.42# 74.93 ± 3.07 74.73 ± 1.60 67.81 ± 2.22#,† 39.41 ± 0.71* 35.70 ± 0.82* 30.46 ± 0.50*,# 30.16 ± 0.65* 30.28 ± 0.72* 23.42 ± 0.85*,#,† EDL (mg) Quadriceps (mg). Gastrocnemius Soleus (mg) (mg) 8.44 ± 0.23 134.96 ± 1.37 11.70 ± 0.73† 152.09 ± 2.07† 11.96 ± 0.29# 177.87 ± 2.12# 12.38 ± 0.43 181.67 ± 10.05 12.16 ± 0.39 171.46 ± 6.56 13.66 ± 0.18#,† 146.55 ± 4.90† 6.73 ± 0.17* 109.41 ± 1.72* 7.95 ± 0.26* 105.93 ± 3.09* 7.01 ± 0.36* 67.85 ± 0.79*,# 8.38 ± 0.24* 70.45 ± 1.42* 8.46 ± 0.26* 63.95 ± 1.97* 6.25 ± 0.19*,#,† 45.14 ± 2.14*,#,†
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