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

Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocy-tic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treat-ment. 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) fl -oxida-tion resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA fl-oxidation pathway in CS-Dsg2-/- mice. Reactivation of PPARa by fenofibrate or AAV9-Ppara significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR-4EBP1-PPARa-dependent FA fl-oxidation contributes to myocardial lipid accumulation in ACM and PPARa may be a potential target for curative treatment of ACM. 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Arrhythmogenic cardiomyopathy (ACM) is a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, resulting in cardiac lipid accumulation. The accumulation of fat is caused by impaired fatty acid oxidation, which is related to the decline of mTOR signaling. Reactivation of PPARa can alleviate lipid accumulation and restore cardiac function, suggesting it as a potential target for curative treatment of ACM.