亨廷顿病YAC128模型脑和骨骼肌年龄相关线粒体改变

IF 5.4 Q1 GERIATRICS & GERONTOLOGY
Kristina Bečanović, Muhammad Asghar, Izabella Gadawska, Shiny Sachdeva, David Walker, Eduardo R Lazarowski, Sonia Franciosi, Kevin H J Park, Hélène C F Côté, Blair R Leavitt
{"title":"亨廷顿病YAC128模型脑和骨骼肌年龄相关线粒体改变","authors":"Kristina Bečanović,&nbsp;Muhammad Asghar,&nbsp;Izabella Gadawska,&nbsp;Shiny Sachdeva,&nbsp;David Walker,&nbsp;Eduardo R Lazarowski,&nbsp;Sonia Franciosi,&nbsp;Kevin H J Park,&nbsp;Hélène C F Côté,&nbsp;Blair R Leavitt","doi":"10.1038/s41514-021-00079-2","DOIUrl":null,"url":null,"abstract":"<p><p>Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington's disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"7 1","pages":"26"},"PeriodicalIF":5.4000,"publicationDate":"2021-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516942/pdf/","citationCount":"8","resultStr":"{\"title\":\"Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.\",\"authors\":\"Kristina Bečanović,&nbsp;Muhammad Asghar,&nbsp;Izabella Gadawska,&nbsp;Shiny Sachdeva,&nbsp;David Walker,&nbsp;Eduardo R Lazarowski,&nbsp;Sonia Franciosi,&nbsp;Kevin H J Park,&nbsp;Hélène C F Côté,&nbsp;Blair R Leavitt\",\"doi\":\"10.1038/s41514-021-00079-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington's disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.</p>\",\"PeriodicalId\":19334,\"journal\":{\"name\":\"NPJ Aging and Mechanisms of Disease\",\"volume\":\"7 1\",\"pages\":\"26\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2021-10-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516942/pdf/\",\"citationCount\":\"8\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NPJ Aging and Mechanisms of Disease\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1038/s41514-021-00079-2\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GERIATRICS & GERONTOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Aging and Mechanisms of Disease","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s41514-021-00079-2","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
引用次数: 8

摘要

线粒体功能障碍和生物能量衰竭是亨廷顿舞蹈病(HD)和衰老的常见病理标志。在本研究中,我们使用YAC128小鼠HD模型来检测突变型亨廷顿蛋白对脑和骨骼肌中与衰老相关的线粒体参数的影响。我们对YAC128小鼠线粒体DNA变化进行了横断面自然历史研究。在这里,我们首先表明,在老龄小鼠纹状体神经元细胞体附近的轴突和树突区域,线粒体体积分数似乎增加。线粒体DNA拷贝数(mtDNAcn)作为线粒体生物发生和功能的代用指标。我们观察到mtDNAcn以组织特异性的方式随年龄和基因型发生显著变化。我们发现衰老与纹状体和骨骼肌的mtDNAcn呈正相关,而与皮质无关。值得注意的是,YAC128小鼠皮质和骨骼肌中的mtDNAcn含量较低。我们进一步表明,在年轻和年老的YAC128和WT小鼠的纹状体和骨骼肌组织中都存在mtDNA缺失。在小鼠中横断面跟踪基因表达水平使我们能够确定年龄和基因型对线粒体相关基因转录变异的贡献。这些发现为线粒体动力学在脑和骨骼肌HD发病机制中的作用提供了见解,并表明骨骼肌组织中的mtDNAcn可能是一个潜在的生物标志物,应该在人类HD中进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.

Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.

Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.

Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.

Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington's disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
自引率
0.00%
发文量
0
审稿时长
8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信