Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands.
FASEB J. 2019 Jul;33(7):8110-8124. doi: 10.1096/fj.201802488R. Epub 2019 Apr 1.
The C57BL/10ScSn-/J (BL10-) mouse has been the most commonly used model for Duchenne muscular dystrophy (DMD) for decades. Their muscle dysfunction and pathology is, however, less severe than in patients with DMD, which complicates preclinical studies. Recent discoveries indicate that disease severity is exacerbated when muscular dystrophy mouse models are generated on a DBA2/J genetic background. Knowledge on the natural history of animal models is pivotal for high-quality preclinical testing. However, for BL10- mice on a DBA2/J background (D2-), limited data are available. We addressed this gap in the natural history knowledge. First, we compared histopathological aspects in skeletal muscles of young D2-, BL10-, and wild-type mice. Pathology was more pronounced in D2- mice and differed in severity between muscles within individuals. Secondly, we subjected D2- mice to a functional test regime for 34 weeks and identified that female D2- mice outperform severely impaired males, making females less useful for functional preclinical studies. Direct comparisons between 10- and 34-wk-old D2- mice revealed that disease pathology ameliorates with age. Heart pathology was progressive, with some features already evident at a young age. This natural history study of the D2- mouse will be instrumental for experimental design of future preclinical studies.-Van Putten, M., Putker, K., Overzier, M., Adamzek, W. A., Pasteuning-Vuhman, S., Plomp, J. J., Aartsma-Rus, A. Natural disease history of the D2- mouse model for Duchenne muscular dystrophy.
C57BL/10ScSn-/J（BL10-）小鼠作为杜氏肌营养不良症（DMD）模型已被使用数十年。然而，其肌肉功能障碍和病理变化比 DMD 患者要轻，这使得临床前研究变得复杂。最近的发现表明，当在 DBA2/J 遗传背景下生成肌营养不良症小鼠模型时，疾病的严重程度会加剧。了解动物模型的自然病史对于高质量的临床前测试至关重要。然而，对于 DBA2/J 背景下的 BL10- 小鼠（D2-），可用的自然病史数据有限。我们填补了这一空白。首先，我们比较了年轻的 D2-、BL10- 和野生型小鼠骨骼肌的组织病理学方面。D2- 小鼠的病理学表现更为明显，且个体内不同肌肉的严重程度存在差异。其次，我们对 D2- 小鼠进行了 34 周的功能测试，发现雌性 D2- 小鼠的表现优于严重受损的雄性，因此雌性小鼠在功能临床前研究中用处不大。将 10 周龄和 34 周龄的 D2- 小鼠进行直接比较发现，疾病病理学随着年龄的增长而改善。心脏病理学呈进行性发展，在年轻时就已经出现一些特征。这项 D2- 小鼠的自然病史研究将为未来临床前研究的实验设计提供重要依据。-Van Putten, M., Putker, K., Overzier, M., Adamzek, W. A., Pasteuning-Vuhman, S., Plomp, J. J., Aartsma-Rus, A. D2- 小鼠模型用于杜氏肌营养不良症的自然病史研究。
