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Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation
Jason C Choi1, Wei Wu, Antoine Muchir
1Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Background:
Mutations in LMNA gene cause cardiomyopathy, for which mechanistic insights are lacking.
Results:
Dusp4 expression is enhanced in hearts with LMNA cardiomyopathy, and its overexpression in mice causes it by activating AKT-mTOR signaling that impairs autophagy.
Conclusions:
Dusp4 causes cardiac dysfunction and may contribute to the development of LMNA cardiomyopathy.
Significance:
Revealing pathogenic mechanisms of LMNA cardiomyopathy is essential for the development of mechanism-based therapies. Mutations in the lamin A/C gene (LMNA) cause a diverse spectrum of diseases, the most common of which is dilated cardiomyopathy often with skeletal muscular dystrophy. Lamin A and C are fundamental components of the nuclear lamina, a dynamic meshwork of intermediate filaments lining the nuclear envelope inner membrane. Prevailing evidence suggests that the nuclear envelope functions as a signaling node and that abnormality in the nuclear lamina leads to dysregulated signaling pathways that underlie disease pathogenesis. We previously showed that activated ERK1/2 in hearts of a mouse model of LMNA cardiomyopathy (Lmna(H222P/H222P) mice) contributes to disease, but the complete molecular pathogenesis remains poorly understood. Here we uncover a pathogenic role of dual specificity phosphatase 4 (Dusp4), which is transcriptionally induced by ERK1/2. Dusp4 is highly expressed in the hearts of Lmna(H222P/H222P) mice, and transgenic mice with cardiac-selective overexpression of Dusp4 display heart dysfunction similar to LMNA cardiomyopathy. In both primary tissue and cell culture models, overexpression of Dusp4 positively regulates AKT-mTOR signaling, resulting in impaired autophagy. These findings identify a pathogenic role of Dusp4 in LMNA cardiomyopathy.
Insights
Dual specificity phosphatase 4 (Dusp4) is upregulated in lamin A/C (LMNA) cardiomyopathy and causes cardiac dysfunction by activating AKT-mTOR signaling and impairing autophagy.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Diseases
Background:
- Mutations in the lamin A/C gene (LMNA) are a primary cause of inherited cardiomyopathies, but their underlying molecular mechanisms remain unclear.
- Lamin A/C proteins are crucial for nuclear lamina structure and function, with disruptions leading to signaling pathway dysregulation.
- Previous research indicated a role for activated ERK1/2 in LMNA cardiomyopathy, yet a complete pathogenic pathway was missing.
Purpose of the Study:
- To investigate the role of dual specificity phosphatase 4 (Dusp4) in the pathogenesis of LMNA cardiomyopathy.
- To elucidate the molecular mechanisms by which Dusp4 contributes to cardiac dysfunction in LMNA cardiomyopathy.
- To identify potential therapeutic targets for LMNA-related heart disease.
Main Methods:
- Analysis of Dusp4 expression in hearts of a mouse model of LMNA cardiomyopathy (Lmna(H222P/H222P) mice).
- Generation and analysis of transgenic mice with cardiac-selective overexpression of Dusp4.
- In vitro studies using primary tissue and cell culture models to assess Dusp4's effect on signaling pathways and autophagy.
Main Results:
- Dusp4 expression is significantly elevated in the hearts of mice with LMNA cardiomyopathy.
- Cardiac-specific overexpression of Dusp4 in mice recapitulates key features of LMNA cardiomyopathy, including heart dysfunction.
- Dusp4 overexpression activates the AKT-mTOR signaling pathway, leading to impaired autophagic flux in cardiac cells.
Conclusions:
- Dusp4 plays a direct pathogenic role in LMNA cardiomyopathy.
- Dusp4-mediated activation of AKT-mTOR signaling and subsequent autophagy impairment contribute to cardiac dysfunction.
- Dusp4 represents a potential therapeutic target for mechanism-based treatment of LMNA cardiomyopathy.
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