METTL7B-induced histone lactylation prevents heart failure by ameliorating cardiac remodelling.

Introduction: Lactylation is important for a variety of biological activities. It is reported that Class I histone deacetylases (HDAC1-3) are histone lysine delactylases. However, the role of lactylation in cardiac remodelling remains uncertain.

Objectives: To explore a novel regulator of lactylation and elucidate their functional mechanisms in cardiac remodelling and heart failure.

Methods: GSE36961, GSE141910 and GSE174691 related to HCM (hypertrophic cardiomyopathy) were separately acquired from Gene expression Omnibus. Candidate genes related to both HCM and histone lactylation were determined by the intersection of DEGs (differentially expressed genes) and module genes sifted by WGCNA (Weighted Gene Co-Expression Network Analysis). METTL7B was screened out and its expression in hypertrophic myocardium was measured by qRT-PCR and western blotting. Furthermore, immunofluorescence, immunoprecipitation, and RNA pull-down assays were utilized to identify the biological functions of METTL7B. The myocardial biopsy of HCM and transverse aortic constriction (TAC) mouse model were performed to analyze the effects of METTL7B on cardiac remodelling in vivo.

Results: We observed that the expression of METTL7B was down-regulated in hypertrophic myocardium, and the lactylation level was increased during the early stage and falling rapidly in the process of cardiac remodelling. Furthermore, we demonstrated that sodium lactate (NALA) administration fulfil a protective role on cardiac remodelling, and METTL7B alleviates cardiac remodelling and improves heart function by maintaining the activation of histone lactylation possibly at the later stage. Impressively, METTL7B suppressed the expression of USP38 via m6A dependent mRNA degradation, resulting in increasing ubiquitylation of HDAC3, which is a proven histone lysine delactylases.

Conclusion: We identifed METTL7B as a potential therapeutic target for myocardial remodelling and showed that it played a critical role in the promotion of myocardial lactylation, which is beneficial for improvement of cardiac function and attenuation of cardiac remodelling.