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Published on: August 8, 2022
Heterozygous LmnadelK32 mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency
Marie-Elodie Cattin1, Anne T Bertrand, Saskia Schlossarek
1Inserm, U974, Paris F-75013, France.
Insights
Heterozygous LMNA mutations in mice cause dilated cardiomyopathy (DCM) through two distinct phases involving lamin A/C levels and ubiquitin-proteasome system impairment, leading to heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Cellular Pathology
Background:
- Dilated cardiomyopathy (DCM) is characterized by left ventricular (LV) enlargement and impaired systolic function, a leading cause of heart failure.
- Mutations in the LMNA gene, encoding nuclear envelope proteins lamins A/C, are linked to DCM, often accompanied by conduction and rhythm abnormalities.
- The precise molecular mechanisms connecting LMNA mutations to DCM pathogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the cardiac phenotype and underlying pathomechanisms in heterozygous Lmna(ΔK32/+) (Het) knock-in mice carrying a human LMNA mutation.
- To elucidate the temporal changes in lamin A/C levels and the role of the ubiquitin-proteasome system (UPS) in disease progression.
- To establish a relevant preclinical model for studying LMNA-associated DCM.
Main Methods:
- Generation and characterization of heterozygous Lmna(ΔK32/+) knock-in mice.
- Assessment of cardiac function, histology, and protein levels of lamin A/C.
- Cross-breeding with Ub(G76V)-GFP reporter mice to evaluate UPS activity in the heart.
- Functional assessment of engineered heart tissue with impaired UPS.
Main Results:
- Het mice exhibited a cardiac-specific phenotype, developing DCM and mortality between 35 and 70 weeks of age.
- Early-stage Het hearts showed reduced lamin A/C due to degradation of toxic mutant protein, likely causing remodeling via haploinsufficiency.
- Late-stage Het hearts displayed normalized lamin A/C levels but increased toxic mutant protein, correlating with impaired UPS function and nuclear aggregation.
- Heart-specific UPS impairment was identified in Het mice, contributing to cardiac dysfunction.
Conclusions:
- Het mice represent the first heterozygous knock-in model demonstrating a cardiac-specific phenotype relevant to LMNA-associated DCM.
- Cardiomyocytes in Het mice face a dual challenge: managing mutant lamin A/C degradation and compensating for lamin haploinsufficiency, both culminating in DCM.
- These findings highlight the complex interplay between protein degradation pathways and nuclear envelope integrity in the pathogenesis of inherited cardiomyopathies.
Abstract:
Dilated cardiomyopathy (DCM) associates left ventricular (LV) dilatation and systolic dysfunction and is a major cause of heart failure and cardiac transplantation. LMNA gene encodes lamins A/C, proteins of the nuclear envelope. LMNA mutations cause DCM with conduction and/or rhythm defects. The pathomechanisms linking mutations to DCM remain to be elucidated. We investigated the phenotype and associated pathomechanisms of heterozygous Lmna(ΔK32/+) (Het) knock-in mice, which carry a human mutation. Het mice developed a cardiac-specific phenotype. Two phases, with two different pathomechanisms, could be observed that lead to the development of cardiac dysfunction, DCM and death between 35 and 70 weeks of age. In young Het hearts, there was a clear reduction in lamin A/C level, mainly due to the degradation of toxic ΔK32-lamin. As a side effect, lamin A/C haploinsufficiency probably triggers the cardiac remodelling. In older hearts, when DCM has developed, the lamin A/C level was normalized and associated with increased toxic ΔK32-lamin expression. Crossing our mice with the Ub(G76V)-GFP ubiquitin-proteasome system (UPS) reporter mice revealed a heart-specific UPS impairment in Het. While UPS impairment itself has a clear deleterious effect on engineered heart tissue's force of contraction, it also leads to the nuclear aggregation of viral-mediated expression of ΔK32-lamin. In conclusion, Het mice are the first knock-in Lmna model with cardiac-specific phenotype at the heterozygous state. Altogether, our data provide evidence that Het cardiomyocytes have to deal with major dilemma: mutant lamin A/C degradation or normalization of lamin level to fight the deleterious effect of lamin haploinsufficiency, both leading to DCM.
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