期刊
SCIENTIFIC REPORTS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-50550-0
关键词
-
资金
- Swedish Research Council
- Association Francaise contre les Myopathies
- Royal Physiographic Society
- Crafoord Foundation
- Greta and Johan Kock Foundation
- Linnea and Josef Carlsson Foundation
- Fanny Ekdahl Foundation
Deficiency of laminin alpha 2 chain leads to a severe form of congenital muscular dystrophy (LAMA2-CMD), and dystrophic symptoms progress rapidly in early childhood. Currently, there is no treatment for this detrimental disorder. Development of therapies is largely hindered by lack of understanding of mechanisms involved in the disease initiation and progress, both in patients but also in mouse models that are commonly used in the preclinical setup. Here, we unveil the first pathogenic events and characterise the disease development in a mouse model for LAMA2-CMD (dy(3K)/dy(3K)), by analysing muscles at perinatal, neonatal and postnatal stages. We found that apoptotic muscle fibres were present as early as postnatal day 1. Other typical dystrophic hallmarks (muscle degeneration, inflammation, and extensive production of the extracellular matrix proteins) were clearly evident already at postnatal day 4, and the highest degree of muscle deterioration was reached by day 7. Interestingly, the severe phenotype of limb muscles partially recovered on days 14 and 21, despite worsening of the general condition of the dy(3K)/dy(3K )mouse by that age. We found that masticatory muscles were severely affected in dy(3K)/dy(3K) mice and this may be an underlying cause of their malnutrition, which contributes to death around day 21. We also showed that several signalling pathways were affected already in 1-day-old dy(3K)/dy(3K) muscle. Therapeutic tests in the dy(3K)/dy(3K) mouse model should therefore be initiated shortly after birth, but should also take into account timing and correlation between regenerative and pathogenic events.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据