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Abstract
Duchenne muscular dystrophy, one of the most common lethal genetic disorders, is caused by mutations in the DMD gene and a lack of dystrophin protein. In most DMD patients and animal models, sporadic dystrophin-positive muscle fibres, called revertant fibres (RFs), are observed in otherwise dystrophin-negative backgrounds. RFs are thought to arise from skeletal muscle precursor cells and clonally expand with age due to the frequent regeneration of necrotic fibres. Here we examined the effects of genetic background on muscle regeneration and RF expansion by comparing dystrophin-deficient mdx mice on the C57BL/6 background (mdx-B6) with those on the DBA/2 background (mdx-DBA), which have a more severe phenotype. Interestingly, mdx-DBA muscles had significantly lower RF expansion than mdx-B6 in all age groups, including 2, 6, 12, and 18 months. The percentage of centrally nucleated fibres was also significantly lower in mdx-DBA mice compared to mdx-B6, indicating that less muscle regeneration occurs in mdx-DBA. Our study aligns with the model that RF expansion reflects the activity of precursor cells in skeletal muscles, and it serves as an index of muscle regeneration capacity.
Highlights
To compare the effect of different genetic backgrounds on the long-term regenerative capacity of dystrophic muscles between mdx on the DBA/2 background (mdx-DBA) and mdx-B6 mice, we analysed the number of centrally nucleated fibres (CNFs) and developmental myosin heavy chain (MHCd)-positive myofibres, indicative of cumulative and current muscle regeneration, respectively, at 2, 6, 12, and 18 months of age
RFs are observed in Duchenne muscular dystrophy (DMD) patients and animal models and have been reported to expand with age in dystrophic mouse models[7,8,12]
It is hypothesized that when myofibres surrounding the area around an RF degenerate, revertant satellite stem cells encoding an altered splicing pattern for dystrophin expression become activated during the regeneration process and cause the clonal expansion of RFs
Summary
Mdx-B10 mice display a much milder dystrophic phenotype, lower accumulation of fat and fibrosis, and increased skeletal muscle mass for most of their lifespan[20,23,24] These differences are likely due to the excellent regenerative capacity of mdx-B10 mice and increased expression of utrophin, a dystrophin homolog protein[25,26,27,28]. Expansion of RFs, which are generated from proliferating myogenic cells, is likely to be lower in mdx-DBA than in mdx-B6 To test this hypothesis, we examined muscle regeneration and RF expression/expansion activities during the course of degeneration between mdx models with different genetic backgrounds (mdx-B6 and mdx-DBA/2 mice) from 2 to 18 months of age. The present study demonstrates that genetic backgrounds affect the regenerative capacity of skeletal muscles and the capacity of RF expansion
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