METTL3 modulates autophagy by targeting TFEB in myocardial hypertrophy

Abstract Pathological myocardial hypertrophy is not only the central link of cardiac remodeling, but also an independent risk factor for heart failure. It has been shown that autophagy is closely related to myocardial hypertrophy. The m6A modification element (METTL3 and ALKBH5) interact with TFEB and controls autophagy. The major focus of this study was to find how m6A modification and TFEB mediate autophagy in myocardial hypertrophy progression. Here, we show that down-regulation of TFEB expression, impaired autophagy and increased apoptosis in pathological myocardial hypertrophy. There were differences in the methylation level of m6A and the expression of METTL3, ALKBH5 and HNRNPD in pathological myocardial hypertrophy. Increased expression of METTL3 affects the expression of TFEB in hypertrophic cardiomyocytes by regulating the binding of ALKBH5, HNRNPD and TFEB pre-mRNA. TFEB can reverse-regulate the expression of METTL3, ALKBH5 and HNRNPD in hypertrophic cardiomyocytes. This study shows that in the pathological myocardial hypertrophy model, the increase of METTL3 level can inhibit the binding of ALKBH5 and TFEB pre-mRNA, thus promoting the binding of HNRNPD and TFEB pre-mRNA, which leads to the rapid degradation of TFEB mRNA, inhibiting the expression of TFEB, causing damage to the autophagy pathway of cardiac hypertrophic cells, and finally lead to myocardial injury.