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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Mouse model of desmin-related cardiomyopathy
1Divisions of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
Background:
The consequence of upregulation of desmin in the heart is unknown. Mutations in desmin have been linked to desmin-related myopathy (DRM), which is characterized by abnormal intrasarcoplasmic accumulation of desmin, but direct causative evidence that a desmin mutation leads to aberrant intrasarcoplasmic desmin accumulation, aggregation, and cardiomyopathy is lacking.
Methods And Results:
Multiple transgenic mouse lines that expressed either murine wild-type desmin or a 7-amino acid deletion (R173 through E179) desmin (D7-des) mutation linked to DRM were made. The distribution of desmin protein was unchanged, and no overt phenotype was detected in the wild-type desmin transgenic mice. In contrast, the D7-des mouse heart showed aberrant intrasarcoplasmic and electron-dense granular filamentous aggregates that were desmin-positive and characteristic of human DRM. The desmin filament network was significantly disrupted, and myofibril alignment was visibly compromised. Although systolic function at the whole-organ level was substantially conserved in the young adult animals, the ability of the heart to respond to beta-agonist stimulation, as measured in the intact animal, was significantly blunted.
Conclusions:
Upregulation of desmin protein at moderate levels is not detrimental. However, the D7-des mutation is dominant negative, and expression of the mutant protein leads to the appearance of aggregates that are characteristic of and diagnostic for human desmin-related cardiomyopathy.
Insights
A desmin mutation causes abnormal protein aggregates in the heart, leading to desmin-related cardiomyopathy. Moderate desmin protein upregulation alone does not harm heart function.
Area of Science:
- Cardiovascular Biology
- Muscle Physiology
- Genetic Pathology
Background:
- The functional impact of increased desmin protein in the heart remains unclear.
- Desmin mutations are associated with desmin-related myopathy (DRM), but direct causal links to aberrant protein accumulation and cardiomyopathy are not established.
Purpose of the Study:
- To investigate the in vivo consequences of a specific desmin mutation linked to desmin-related myopathy.
- To determine if desmin mutations cause aberrant protein aggregation and cardiac dysfunction.
Main Methods:
- Generation of transgenic mouse models expressing either wild-type desmin or a desmin mutation (D7-des).
- Analysis of desmin protein distribution, cardiac morphology, and function in transgenic mice.
- Assessment of cardiac response to beta-agonist stimulation.
Main Results:
- Transgenic mice expressing wild-type desmin showed no significant changes.
- Mice with the D7-des mutation exhibited desmin-positive aggregates characteristic of human DRM.
- The D7-des mutation disrupted the desmin filament network, compromised myofibril alignment, and blunted the heart's response to stimulation.
Conclusions:
- Moderate desmin protein upregulation is not detrimental to heart function.
- The D7-des mutation acts as a dominant negative, causing aggregates diagnostic of human desmin-related cardiomyopathy.
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