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Cardiac dysfunction in the R6/2 mouse model of Huntington's disease
Michael J Mihm1, Deborah M Amann, Brandon L Schanbacher
1Center for Cardiovascular Medicine, Columbus Children's Research Institute, 700 Children's Drive, Columbus, OH 43205, USA.
Insights
Mutant huntingtin protein causes cardiac dysfunction and failure in a mouse model of Huntington's disease (HD). This suggests mutant huntingtin may directly impact heart health, warranting further investigation in humans.
Area of Science:
- Cardiovascular Biology
- Neurodegenerative Diseases
- Molecular Genetics
Background:
- Huntington's disease (HD) is linked to neuronal dysfunction due to energetic deficits caused by mutant huntingtin.
- Cardiovascular disease is a leading cause of mortality in HD patients, but the direct role of mutant huntingtin in cardiac dysfunction is unclear.
Purpose of the Study:
- To investigate if mutant huntingtin expression is sufficient to induce cardiac dysfunction.
- To evaluate the direct cardiotoxic effects of mutant huntingtin in a transgenic mouse model of HD.
Main Methods:
- Utilized the R6/2 transgenic mouse model of Huntington's disease.
- Assessed cardiac function using echocardiography.
- Examined cardiac remodeling, mitochondrial structure, and molecular changes (acetylation, nitration) via electron microscopy and biochemical analyses.
Main Results:
- R6/2 mice exhibited progressive cardiac dysfunction from 8 weeks, leading to severe failure by 12 weeks.
- Observed significant elevations of mutant huntingtin in cardiac myocytes, altered mitochondrial ultrastructure, and increased cardiac lysine acetylation and protein nitration.
- These molecular changes were associated with impaired cardiac performance.
Conclusions:
- Mutant huntingtin expression induces potent cardiotoxic effects and cardiac failure in mice.
- Cardiac complications may be a significant feature of this HD model.
- Further research into the cardiotropic effects of mutant huntingtin in humans is warranted.
Abstract:
Recent evidence suggests that mutant huntingtin protein-induced energetic perturbations contribute to neuronal dysfunction in Huntington's disease (HD). Given the ubiquitous expression of huntingtin, other cell types with high energetic burden may be at risk for HD-related dysfunction. Early-onset cardiovascular disease is the second leading cause of death in HD patients; a direct role for mutant huntingtin in this phenomenon remains unevaluated. Here we tested the hypothesis that expression of mutant huntingtin is sufficient to induce cardiac dysfunction, using a well-described transgenic model of HD (line R6/2). R6/2 mice developed cardiac dysfunction by 8 weeks of age, progressing to severe failure at 12 weeks, assessed by echocardiography. Limited evidence of cardiac remodeling (e.g. hypertrophy, fibrosis, apoptosis, beta(1) adrenergic receptor downregulation) was observed. Immunogold electron microscopy demonstrated significant elevations in nuclear and mitochondrial polyglutamine presence in the R6/2 myocyte. Significant alterations in mitochondrial ultrastructure were seen, consistent with metabolic stress. Increased cardiac lysine acetylation and protein nitration were observed and were each significantly associated with impairments in cardiac performance. These data demonstrate that mutant huntingtin expression has potent cardiotoxic effects; cardiac failure may be a significant complication of this important experimental model of HD. Investigation of the potential cardiotropic effects of mutant huntingtin in humans may be warranted.
