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

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.