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