TMEM43 overexpression improves arrhythmogenic cardiomyopathy type 5 phenotype in mice
Presented by: Laura Lalaguna
Presentation time:
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterised by chamber dilation and fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive subtype of ACM is ACM type 5 (ACM5), caused by the missense mutation pS358L in TMEM43 (transmembrane protein 43). The function of TMEM43 and its role in ACM5 are still unknown, hindering the development of effective therapeutic options.
In previous data we observed the interaction between the wild-type (WT) and pS358L forms of TMEM43, suggesting that WT-TMEM43 could quench the detrimental effects of the mutant protein by forming a heterodimer. Therefore, we propose that the overexpression of WT-TMEM43 could be beneficial for ACM5 progression. Using our previously reported transgenic mouse models overexpressing either WT- or pS358L-TMEM43, we have generated a double transgenic mouse overexpressing both forms of the protein. The functional effects were analysed by echocardiography and electrocardiogram at 5, 16 and 24 weeks of age. The results show a significantly increased lifespan in the double transgenic (DT) mice compared to the ones overexpressing the mutant TMEM43. This is accompanied by an improvement in the systolic function of both ventricles, as observed by an increased left ventricular ejection fraction (LVEF) and tricuspid annular plane systolic excursion (TAPSE), which is already evident at 16 weeks of age. In addition, DT mice show fewer cardiac conduction defects, with a reduced p wave and QRS duration and increased QRS amplitude. Furthermore, reduced serum cardiac troponin I levels suggest delayed cardiomyocyte necrosis in DT mice compared to the mutant mice.
Overall, this data provides evidence that an overexpression of WT-TMEM43 delays the onset of ACM5 phenotype and could potentially be a novel therapeutic approach for ACM5.
In previous data we observed the interaction between the wild-type (WT) and pS358L forms of TMEM43, suggesting that WT-TMEM43 could quench the detrimental effects of the mutant protein by forming a heterodimer. Therefore, we propose that the overexpression of WT-TMEM43 could be beneficial for ACM5 progression. Using our previously reported transgenic mouse models overexpressing either WT- or pS358L-TMEM43, we have generated a double transgenic mouse overexpressing both forms of the protein. The functional effects were analysed by echocardiography and electrocardiogram at 5, 16 and 24 weeks of age. The results show a significantly increased lifespan in the double transgenic (DT) mice compared to the ones overexpressing the mutant TMEM43. This is accompanied by an improvement in the systolic function of both ventricles, as observed by an increased left ventricular ejection fraction (LVEF) and tricuspid annular plane systolic excursion (TAPSE), which is already evident at 16 weeks of age. In addition, DT mice show fewer cardiac conduction defects, with a reduced p wave and QRS duration and increased QRS amplitude. Furthermore, reduced serum cardiac troponin I levels suggest delayed cardiomyocyte necrosis in DT mice compared to the mutant mice.
Overall, this data provides evidence that an overexpression of WT-TMEM43 delays the onset of ACM5 phenotype and could potentially be a novel therapeutic approach for ACM5.