Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treatment. It is often caused by mutations in desmosome proteins, with Desmoglein-2 (DSG2) mutations as a common etiology. However, the mechanism underlying the accumulation of fibrofatty in ACM remains unknown, which impedes the development of curative treatment. Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2 (CS-Dsg2(−/−)). Heart failure and cardiac lipid accumulation were observed in CS-Dsg2(−/−) mice. We demonstrated that these phenotypes were caused by decline of fatty acid (FA) β-oxidation resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA β-oxidation pathway in CS-Dsg2(−/−) mice. Reactivation of PPARα by fenofibrate or AAV9-Pparα significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR–4EBP1–PPARα-dependent FA β-oxidation contributes to myocardial lipid accumulation in ACM and PPARα may be a potential target for curative treatment of ACM.