Altered Expression of TMEM43 Causes Abnormal Cardiac Structure and Function in Zebrafish

Area of Science:

• Cardiovascular Biology
• Genetics
• Molecular Medicine

Background:

• Arrhythmogenic cardiomyopathy (ACM) is an inherited heart condition.
• It stems from mutations in the TMEM43 gene, affecting nuclear envelope proteins.
• The precise role of TMEM43 in ACM pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the function of TMEM43 and its disease-associated variants.
• To elucidate the molecular mechanisms underlying TMEM43-related cardiomyopathy.
• To establish a zebrafish model for studying ACM.

Main Methods:

• Generated cardiomyocyte-restricted transgenic zebrafish overexpressing wild-type (WT) and mutant TMEM43 (p.S358L, p.P111L).
• Utilized the Tol2-system for gene delivery.
• Employed CRISPR/Cas9 to create gene knockouts.
• Analyzed cardiac morphology, gene expression, and protein localization.

Main Results:

• Overexpression of WT and p.P111L TMEM43 activated mTOR pathway and ribosome biogenesis, causing cardiomyocyte hypertrophy and enlarged hearts.
• The p.S358L mutant TMEM43 showed instability and cytoplasmic redistribution.
• Both TMEM43 variants induced cardiac morphological defects and ultrastructural myocardial changes.
• CRISPR/Cas9 mutants exhibited age-dependent heart enlargement.

Conclusions:

• TMEM43 variants contribute to ACM through ultrastructural remodeling and transcriptomic alterations.
• These changes lead to structural and functional cardiac defects.
• Zebrafish models effectively recapitulate key features of TMEM43-associated cardiomyopathy.