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Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5. Methods: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. Results: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition. Conclusions: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5 ; his work was supported by grants from the European Union (CardioNeT-ITN-289600 and CardioNext-608027 to Dr Lara-Pezzi), the Spanish Ministry of Economy and Competitiveness (RTI2018-096961-B-I00, SAF2015-65722-R, and SAF2012-31451 to Dr Lara-Pezzi; SAF2015-71863-REDT to Dr Garcia-Pavia), the Spanish Carlos III Institute of Health (PI14/0967 to Dr Garcia-Pavia, CPII14/00027 to Dr Lara-Pezzi; RD012/0042/0066 to Drs Garcia-Pavia and Lara-Pezzi), the Regional Government of Madrid (2010-BMD-2321 "Fibroteam" to Dr Lara-Pezzi), the Isabel Gemio Foundation (Todos somos Raros grant to Dr Garcia-Pavia), and the Spanish Society of Cardiology (2014 Basic Research Grant to Dr Garcia-Pavia). This work was also supported by the Plan Estatal de I+D+I 2013-2016–European Regional Development Fund (FEDER) "A way of making Europe," Spain