Therapeutic potential of wild type TMEM43 overexpression in a mouse model of arrhythmogenic cardiomyopathy type 5

Abstract Background and purpose Arrhythmogenic cardiomyopathy type 5 (ACM5) is the most severe subtype of arrhythmogenic cardiomyopathy, caused by a point mutation in TMEM43 (p.S358L). Pathologically, the disease is characterised by dilation of the cardiac chambers and fibro-fatty replacement of the myocardium, which results in heart failure and sudden cardiac death. The function of TMEM43 and the molecular mechanism underlying ACM5 are very poorly understood, precluding the development of effective therapeutic options. We have previously 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. Methods and results Using our 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 electrocardiography at 5, 16 and 24 weeks of age. The lifespan of double transgenic (DT) mice increased by 10 weeks compared to mice overexpressing the mutant TMEM43 (p<0.0001). Echocardiography results show an improved systolic function of both ventricles, as observed by an increased left ventricular ejection fraction (LVEF, p<0.001) and tricuspid annular plane systolic excursion (TAPSE, p<0.01), which is already evident at 16 weeks of age. This is accompanied by an improvement in cardiac conduction, with a reduced p wave duration (p<0.001) and QRS duration (p<0.001) and increased QRS amplitude (p<0.0001) in DT mice compared to the mutant mice. In addition, histological analysis of heart samples shows a reduced fibrotic content in the myocardium of DT mice at 24 weeks of age (p<0.0001). Furthermore, the delayed raise in serum cardiac troponin I levels suggests cardiomyocyte necrosis is also delayed in the therapeutic mouse model. Conclusion 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. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Spanish Ministry of Science and Innovation