Sex-dependent mild cardiac dysfunction and neurometabolic abnormalities in a model of Huntington's disease.

IF 3.6 3区医学 Q2 CELL BIOLOGY

Disease Models & Mechanisms Pub Date : 2026-09-01 Epub Date: 2026-09-30 DOI:10.1242/dmm.052922

Kenna L R Hynes, Thomas M O'Brien, Jenna Hanrahan, Rachel Neita, T Nadine Burry, Michael R Hayden, Matthew P Parsons, Amber L Southwell, Lindsay S Cahill

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Abstract

Huntington's disease (HD) is a neurodegenerative disease with progressive decline in psychiatric, motor and cognitive symptoms. Hallmarks of HD include brain volume loss and abnormal metabolism. However, HD is a multi-system disorder, and the impact on other organ systems is poorly understood. Using high-frequency ultrasound and nuclear magnetic resonance, we studied cardiac function (n=9-11 mice/genotype/sex) and brain metabolism (n=10 mice/genotype/sex) in a humanized transgenic mouse model of HD (Hu97/18 mice) at 12 months of age. The assessments were conducted in different cohorts and analyzed separately. Compared to controls (Hu18/18 mice), Hu97/18 mice showed a decrease in the left ventricle ejection fraction in both sexes and an increase in the E/A ratio (E wave/A wave diastolic filling) in females, indicative of mild cardiac dysfunction. The relative concentrations of several metabolites in the brain were altered in Hu97/18 mice, compared to those in Hu18/18 mice, and depended on sex and brain region. These findings are consistent with clinical features observed in human HD, supporting use of the Hu97/18 model for investigation of pathophysiology in HD in multiple organ systems. It also highlights the importance of studying both sexes in HD research.

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亨廷顿氏病模型的性别依赖性轻度心功能障碍和神经代谢异常

亨廷顿氏病（HD）是一种神经退行性疾病，伴有精神、运动和认知症状的进行性下降。HD的特征包括脑容量减少和代谢异常。然而，HD是一种多系统疾病，对其他器官系统的影响知之甚少。采用高频超声和核磁共振技术，研究了12月龄人源化转基因HD小鼠模型（Hu97/18小鼠）的心功能（n=9-11只/基因型/性别）和脑代谢（n=10只/基因型/性别）。评估在不同的队列中进行，并分别进行分析。与对照组（Hu18/18小鼠）相比，Hu97/18小鼠雌雄左心室射血分数均下降，雌性左心室E/ a比（E波/ a波舒张充盈）升高，提示心功能轻度障碍。与Hu18/18小鼠相比，Hu97/18小鼠大脑中几种代谢物的相对浓度发生了变化，并且与性别和大脑区域有关。这些发现与在人类HD中观察到的临床特征一致，支持使用Hu97/18模型来研究HD多器官系统的病理生理。它还强调了在HD研究中研究两性的重要性。

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来源期刊

Disease Models & Mechanisms 医学-病理学

CiteScore

6.60

自引率

7.00%

发文量

203

审稿时长

6-12 weeks

期刊介绍： Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.