Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F
Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F
复制标题
2D和2F型肢带型肌营养不良症小鼠模型的自然病史
作者：
S. Pasteuning;K. Putker;C. T. Tanganyika;J. W. Boertje;L. van Vliet;M. Overzier;J. Plomp;Annemieke Aartsma;M. van Putten
2D 和 2F 型肢带型肌营养不良症（LGMD 2D 和 2F）是常染色体隐性遗传疾病，分别由 α 和 δ 肌聚糖基因突变引起，导致严重的肌肉无力和退化。该疾病的病因已得到充分表征，并且许多动物模型可用于临床前研究以测试潜在的治疗干预措施。为了促进从药物发现到临床试验的过渡，为这些小鼠模型收集了标准化程序和自然疾病史数据。实施 TREAD-NMD 标准化操作程序，我们对 LGMD2D (SGCA-null)、LGMD2F (SGCD-null) 和野生型 (C57BL/6J) 小鼠进行五次功能测试，从 4 周龄到 32 周龄。为了评估功能测试方案是否干扰疾病病理学，久坐组也被纳入其中。 34周龄时进行胫骨前肌的肌肉生理学测试。对骨骼肌和心脏的肌肉组织病理学和基因表达进行了分析。对骨骼肌和心脏的肌肉组织病理学和基因表达进行了分析。小鼠成功完成了功能测试，并且没有干扰疾病病理学。 SGCA 和 SGCD 缺失小鼠的肌肉功能受损并随着时间的推移而下降。有趣的是，雌性 SGCD 缺失小鼠在两次和四次肢体悬挂测试中表现优于雄性，这被证明是评估肌肉功能的最合适的非侵入性测试。胫骨前肌的肌肉生理学测试显示，LGMD 小鼠的比力较低，对偏心诱导损伤的敏感性较高。通过分析肌肉组织病理学和基因表达，我们确定膈肌是 LGMD 菌株中受影响最严重的肌肉。在 SGCD 缺失的小鼠中发现了心脏纤维化，雄性比雌性更严重。我们的研究提供了一个全面的自然历史数据集，这将有助于设计 LGMD2D 和 2F 小鼠的标准化测试和未来的临床前研究。
Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models. Implementing the TREAD-NMD standardized operating procedures, we here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J) mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional test regime interfered with disease pathology, sedentary groups were taken along. Muscle physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Mice successfully accomplished the functional tests, which did not interfere with disease pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over time. Interestingly, female SGCD-null mice outperformed males in the two and four limb hanging tests, which proved the most suitable non-invasive tests to assess muscle function. Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology and gene expression, we identified the diaphragm as the most affected muscle in LGMD strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in females. Our study offers a comprehensive natural history dataset which will be useful to design standardized tests and future pre-clinical studies in LGMD2D and 2F mice.
肌营养不良小鼠模型告诉我们有关 DAPC 及其成分的哪些信息？
影响因子：
3
作者：
Whitmore C
通讯作者：
Whitmore C