Maureen A. Walsh, Amanda S. Latham, Qian Zhang, Robert A. Jacobs, Robert V. Musci, Thomas J. LaRocca, Julie A. Moreno, Kelly S. Santangelo, Karyn L. Hamilton
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Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression.</p>\n </section>\n </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"240 8","pages":""},"PeriodicalIF":5.6000,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.14185","citationCount":"0","resultStr":"{\"title\":\"Non-transgenic guinea pig strains exhibit divergent age-related changes in hippocampal mitochondrial respiration\",\"authors\":\"Maureen A. Walsh, Amanda S. Latham, Qian Zhang, Robert A. Jacobs, Robert V. 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引用次数: 0
摘要
目的：阿尔茨海默病（AD）是最常见的痴呆症。然而，虽然目前已有 150 多种阿尔茨海默病动物模型，但将药物从临床前模型转化为人类治疗方法的工作通常都以失败告终。导致转化率低的一个因素可能是缺乏同时包含人类衰老过程中多种疾病的神经退行性模型。我们以前曾证实，与模拟 "典型 "脑衰老的 PigmEnTed（PET）豚鼠品系相比，哈特里品系会像衰老的人类一样出现注意力缺失症的特征。哈特里也表现出与年龄相关的软骨和骨骼肌损伤。线粒体呼吸受损是细胞衰老和注意力缺失症的驱动因素之一。在认知能力下降的人类中，骨骼肌和大脑呼吸控制的减弱也同时发生。我们以前曾报道过哈特莱人骨骼肌线粒体呼吸与年龄相关的下降。目前尚不清楚大脑中是否同时存在线粒体功能障碍：因此，我们使用高分辨率呼吸测定法评估了 5 个月和 12 个月哈特利豚鼠和 PET 豚鼠的海马线粒体呼吸：与 5 个月的 PET 相比，12 个月的 PET 具有更高的复合物 I 支持线粒体呼吸，这与其体重的增加相一致。与 5 个月的哈特里犬相比，12 个月的哈特里犬体重也有所增加，但复合 I 呼吸量却没有增加。与 5 个月大的哈特莱人相比，12 个月大的哈特莱人的复合 I 线粒体效率较低，线粒体蛋白质则呈代偿性增加，这共同表明随着年龄的增长，线粒体功能会出现障碍：因此，哈特莱可能是一种相关的模型，可用于测试针对线粒体的有前途的疗法，以延缓大脑衰老和注意力缺失症的进展。
Alzheimer’s disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models “typical” brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain.
Methods
Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry.
Results
At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age.
Conclusions
Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression.
期刊介绍：
Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.
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