Fig. 1.

m6A demethylase FTO attenuates cardiac dysfunction by regulating glucose uptake and glycolysis in mice with pressure overload-induced heart failure. a Total m6A peaks identified by MeRIP-seq in sham and TAC mice. b Distribution of m6A peaks throughout mRNA lengths. c Sequence logo representing the consensus motif identified by Discriminative Regular Expression Motif Elicitation (DREME). d Top 10 enriched GO terms from MeRIP-seq data. e KEGG analysis of altered m6A methylation in metabolic mRNAs. f Quantification of m6A methyltransferase, demethylase, and methyl-specific binding protein mRNA levels in left ventricles of mice at 8 weeks (W) post-TAC (n = 6/group). g Immunoblot of FTO protein levels at 8 weeks post-TAC (n = 6/group). h, i Echocardiographic ejection fraction (EF) and fractional shortening (FS) measurements indicating left ventricle function at 8 weeks post-TAC (n = 6–9/group). j Representative images of hematoxylin and eosin (HE), Masson’s trichrome, and wheat germ agglutinin (WGA) staining. k Representative cardiac ¹⁸F-FDG uptake imaging by micro-PET/CT in FTO-overexpressed mice. l, m EF and FS at 8 weeks post-TAC after FTO knockdown (n = 6–10/group). n Representative cardiac ¹⁸F-FDG uptake imaging in mice with FTO knockdown. o Extracellular acidification rates (ECARs) of isolated cardiomyocytes using the Seahorse XF Analyzer. p Glycolytic function (n = 19–24/group). q ATP production (n = 8/group). r Glycolysis diagram with genes affected by m6A methylation (red). s Representative immunoblots of ALDOB, TPI1, PGM2, PGAM2, and DLD (n = 4/group). t Quantification of m6A enrichment of Pgam2 mRNA detected by MeRIP-qPCR (n = 3/group). u Lifetime of Pgam2 mRNA in primary cardiomyocytes by monitoring transcript abundance after transcription inhibition (TI) at different time points (n = 3/group). v Representative immunoblots of GLUT4 and p-AKT (n = 4/group). w Model of FTO regulation of glucose uptake and glycolysis and its potential translational value in HF. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001