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
{"title":"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。","authors":"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","doi":"10.1016/j.ajpath.2025.09.005","DOIUrl":null,"url":null,"abstract":"<p><p>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-Dmd<sup>mdx</sup>/J (B10-mdx) and the more severe D2.B10-Dmd<sup>mdx</sup>/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.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The D2.B10-Dmd<sup>mdx</sup>/J mouse model of DMD exhibits a severe mitochondrial deficiency not observed in the C57BL/10ScSn-Dmd<sup>mdx</sup>/J mouse.\",\"authors\":\"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\",\"doi\":\"10.1016/j.ajpath.2025.09.005\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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-Dmd<sup>mdx</sup>/J (B10-mdx) and the more severe D2.B10-Dmd<sup>mdx</sup>/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.</p>\",\"PeriodicalId\":7623,\"journal\":{\"name\":\"American Journal of Pathology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-09-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ajpath.2025.09.005\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ajpath.2025.09.005","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
The D2.B10-Dmdmdx/J mouse model of DMD exhibits a severe mitochondrial deficiency not observed in the C57BL/10ScSn-Dmdmdx/J mouse.
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.
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.