The D2.B10-Dmdmdx/J mouse model of DMD exhibits a severe mitochondrial deficiency not observed in the C57BL/10ScSn-Dmdmdx/J mouse.

IF 3.6 2区 医学 Q1 PATHOLOGY
Jennifer A Tinklenberg, Jessica Sutton, Rebecca A Slick, Hui Meng, Margaret Haberman, Mariah J Prom, Margaret J Beatka, Tatyana A Vetter, Audrey L Daugherty, Christina Pacak, J Patrick Gonzalez, Michael W Lawlor
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Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in dystrophin deficiency in skeletal/cardiac muscle and progressive loss of function. While the genetic causes of DMD have been thoroughly investigated, the energetic consequences have not been well examined across animal models. Previously, the lab examined mitochondrial function across nemaline myopathy mouse models of varying disease severity; here, mitochondrial phenotypes in DMD are assessed through the comparison of the milder C57BL/10ScSn-Dmdmdx/J (B10-mdx) and the more severe D2.B10-Dmdmdx/J mouse (D2-mdx) mouse models. D2-mdx exhibit a significant decrease in mitochondrial respiration, undetectable ATP concentrations, increased mitochondrial membrane potential, and alterations in electron transport chain enzyme activities. In contrast, B10-mdx show only mild mitochondrial phenotypes, including decreased ATP content. The D2-mdx mouse has genetic modifiers, including LTBP4 and ANXA6, that have been shown to alter DMD severity in humans. However, these modifiers did not account for mitochondrial differences seen in mdx mice. Both models were treated with a microdystrophin AAV gene therapy to assess whether dystrophin restoration rescued mitochondrial phenotypes. Gene therapy attenuated the ATP deficiency in the B10-mdx mice, but only improved mitochondrial membrane potentials in D2-mdx mice. The exact cause of the D2-mdx mitochondrial phenotypes remains unknown, but secondary disease processes that affect mitochondrial phenotypes should be taken into consideration when choosing an animal model for DMD studies.

D2。B10-Dmdmdx/J小鼠模型显示出C57BL/10ScSn-Dmdmdx/J小鼠未观察到的严重线粒体缺陷。
杜氏肌营养不良症(DMD)是由DMD基因突变导致骨骼肌/心肌肌营养不良蛋白缺乏和功能进行性丧失引起的。虽然DMD的遗传原因已被彻底研究,但其能量后果尚未在动物模型中得到很好的检验。此前,该实验室检查了不同疾病严重程度的线虫性肌病小鼠模型的线粒体功能;在这里,通过比较较轻的C57BL/10ScSn-Dmdmdx/J (B10-mdx)和较严重的D2来评估DMD的线粒体表型。B10-Dmdmdx/J小鼠(D2-mdx)模型。D2-mdx表现出线粒体呼吸明显减少,ATP浓度检测不到,线粒体膜电位增加,电子传递链酶活性改变。相比之下,B10-mdx仅表现出轻微的线粒体表型,包括ATP含量降低。D2-mdx小鼠具有基因修饰因子,包括LTBP4和ANXA6,这些基因修饰因子已被证明可以改变人类DMD的严重程度。然而,这些修饰因子并不能解释mdx小鼠的线粒体差异。两种模型均接受微肌营养不良蛋白AAV基因治疗,以评估肌营养不良蛋白恢复是否挽救了线粒体表型。基因治疗减轻了B10-mdx小鼠的ATP缺乏症,但仅改善了D2-mdx小鼠的线粒体膜电位。D2-mdx线粒体表型的确切原因尚不清楚,但在选择用于DMD研究的动物模型时,应考虑影响线粒体表型的继发性疾病过程。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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