Cardiomyocyte Nuclear Pleomorphism in a Mouse Model of Inherited Hypertrophic Cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Biology

Background:

• Mutations in sarcomeric protein genes are a primary cause of human cardiomyopathies and sudden cardiac death.
• Troponin C (cTnC) is crucial for cardiomyocyte calcium regulation and sarcomere function.
• The TNNc1-p.A8V mutation models hypertrophic cardiomyopathy (HCM), impacting cardiac muscle contractility and gene expression.

Purpose of the Study:

• To investigate the hypothesis that myofilament dysfunction, caused by the TNNc1-p.A8V mutation, is associated with morphological and functional changes in cardiomyocyte nuclei.
• To explore the relationship between sarcomeric protein mutations, nuclear morphology, and protein composition within cardiomyocyte nuclei.

Main Methods:

• Utilized a TNNc1-p.A8V knock-in mouse model of hypertrophic cardiomyopathy.
• Performed histological analysis of myocardial tissue and isolated cardiomyocytes to assess nuclear morphology (size, shape).
• Employed immunoblotting to analyze protein expression and localization (cardiac troponin C, histone H4) in heart tissue and nuclei.

Main Results:

• TNNc1-p.A8V mouse hearts exhibited significantly smaller and rounder cardiomyocyte nuclei compared to wild-type controls.
• Nuclear morphological changes were independent of cardiomyocyte size or ploidy.
• Decreased nuclear localization of cardiac troponin C and reduced histone H4 expression were observed in mutant hearts.

Conclusions:

• Pathological myofilament dysfunction resulting from cardiomyopathy-associated mutations can lead to altered cardiomyocyte nuclear morphology.
• Aberrant nuclear protein composition and shape changes are linked to sarcomeric gene mutations in hypertrophic cardiomyopathy.
• Findings suggest a potential role for cardiomyocyte nuclei in the pathogenesis of HCM.