The m6A Demethylase Fto Enhances Susceptibility to Atrial Fibrillation by Demethylating Kcne1 in Aging Mice

ABSTRACT Aging is a risk factor for atrial fibrillation (AF). In 19‐month‐old mice, increases in AF inducibility are associated with enhanced protein levels of fat mass and obesity‐associated protein (Fto), and reduced N6‐methyladenosine (m6A) modification in atrial tissue. Whether Fto‐regulated m6A demethylation is involved in aging‐induced AF remains unclear. AF inducibility and electrophysiology were performed through programmed stimulation and optical mapping. The intensities of slow delayed rectifier potassium currents (IKs) were measured by patch‐clamp. m6A‐sequencing revealed that Kcne1 mRNA was m6A‐demethylated in aging mouse atria. Kcne1 knockdown in 2‐month‐old mice increased AF inducibility. Aging mice with cardiomyocyte‐specific Fto knockout had increased Kcne1 mRNA and protein levels, with reduced susceptibility to AF. Additionally, overexpression of wild‐type Fto, rather than a catalytically inactive mutant in 2‐month‐old mice, reduced Kcne1 protein levels, leading to enhanced IKs current and AF inducibility. Furthermore, the negative relationship between FTO and KCNE1 was confirmed in left atrial appendage samples from AF patients. In iPSC‐derived atrial cardiomyocytes, FTO‐mediated KCNE1 demethylation repressed KCNE1 pre‐mRNA splicing, mRNA nuclear export, and translational efficacy. Collectively, aging‐induced elevation of Fto represses m6A methylation of Kcne1, which in turn leads to reductions in Kcne1 mRNA and protein levels in atrial cardiomyocytes, thereby increasing AF inducibility.