Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by...

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Arrhythmogenic cardiomyopathy (ARVC) is an inherited heart disease causing fibrofatty myocardial replacement, leading to heart failure and sudden cardiac death.
• Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is a severe subtype caused by a p.S358L mutation in TMEM43.
• The precise function, localization, and disease mechanism of TMEM43 remain largely unknown.

Purpose of the Study:

• To characterize the first transgenic mouse model of ARVC5.
• To elucidate the molecular mechanisms underlying TMEM43-mediated ARVC5.
• To explore potential therapeutic interventions for ARVC5.

Main Methods:

• Generated transgenic mice overexpressing wild-type or p.S358L mutant TMEM43 in cardiomyocytes.
• Assessed cardiac function, histology, and molecular interactions in mutant mice.
• Investigated the effects of calcineurin Aβ1 overexpression and GSK3β inhibition in vivo and in vitro.

Main Results:

• TMEM43-S358L mice recapitulated human ARVC5, exhibiting premature death, cardiomyocyte loss, and severe fibrofatty replacement.
• Mutant TMEM43 localized to the nuclear membrane, interacted with emerin and β-actin, and showed cytoplasmic delocalization and reduced interactions.
• GSK3β activation was observed in mutant TMEM43, and its inhibition via calcineurin Aβ1 or chemical inhibitors improved cardiac function and survival in mice and human cells.

Conclusions:

• The p.S358L TMEM43 mutation drives sustained cardiomyocyte death and fibrofatty replacement, characteristic of ARVC5.
• Targeting GSK3β offers a promising therapeutic strategy for ARVC5, improving cardiac function and extending lifespan.
• This study provides a foundation for developing novel treatments for ARVC5 and related cardiomyopathies.