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Published on: March 29, 2024
Depletion of lamina-associated polypeptide 1 from cardiomyocytes causes cardiac dysfunction in mice
Ji-Yeon Shin1, Caroline Le Dour1, Fusako Sera2
1Department of Medicine; College of Physicians & Surgeons; Columbia University; New York, NY USA; Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University; New York, NY USA.
Insights
Lamina-associated polypeptide 1 (LAP1) is crucial for heart function. Cardiomyocyte-specific LAP1 deletion in mice causes left ventricular systolic dysfunction, indicating LAP1
Area of Science:
- Cell Biology
- Cardiovascular Science
- Genetics
Background:
- Lamina-associated polypeptide 1 (LAP1) is an inner nuclear membrane protein.
- Previous studies linked striated muscle LAP1 depletion to muscular dystrophy.
- LAP1 is also found to be depleted in the hearts of these mice.
Purpose of the Study:
- To investigate the cardiac phenotype associated with LAP1 depletion.
- To determine the role of LAP1 in cardiomyocyte function.
- To elucidate the specific contribution of LAP1 in the heart, independent of skeletal muscle pathology.
Main Methods:
- Generation of cardiomyocyte-selective LAP1 knockout mouse models.
- Cardiac echocardiography to assess left ventricular function.
- Cardiac gene expression analysis to identify molecular changes.
Main Results:
- Cardiomyocyte-specific LAP1 knockout mice developed left ventricular systolic dysfunction.
- Abnormal induction of genes associated with cardiomyopathy was observed.
- These mice showed no skeletal muscle pathology, isolating the cardiac effect.
Conclusions:
- Cardiomyocyte LAP1 expression is essential for normal left ventricular function.
- LAP1 deficiency in cardiomyocytes leads to cardiac dysfunction and gene expression changes.
- Findings align with human genetic reports linking LAP1 mutations to cardiomyopathy.
Abstract:
We previously showed that striated muscle-selective depletion of lamina-associated polypeptide 1 (LAP1), an integral inner nuclear membrane protein, leads to profound muscular dystrophy with premature death in mice. As LAP1 is also depleted in hearts of these mice, we examined their cardiac phenotype. Striated muscle-selective LAP1 knockout mice display ventricular systolic dysfunction with abnormal induction of genes encoding cardiomyopathy related proteins. To eliminate possible confounding effects due to skeletal muscle pathology, we generated a new mouse line in which LAP1 is deleted in a cardiomyocyte-selective manner. These mice had no skeletal muscle pathology and appeared overtly normal at 20 weeks of age. However, cardiac echocardiography revealed that they developed left ventricular systolic dysfunction and cardiac gene expression analysis revealed abnormal induction of cardiomyopathy-related genes. Our results demonstrate that LAP1 expression in cardiomyocytes is required for normal left ventricular function, consistent with a report of cardiomyopathy in a human subject with mutation in the gene encoding LAP1.
