The tRNA methyltransferase Mettl1 governs ketogenesis through translational regulation and drives metabolic reprogramming in cardiomyocyte maturation

Following birth, the heart undergoes intricate transitions in response to the altered environment, including shifts in energy metabolism and cytoarchitecture, such as the switch from glucose to lipid utilization and the transformation of fetal-to-adult sarcomeric gene isoforms, all aimed at achieving functional maturation. These adaptations facilitate efficient energy production and cardiac contraction, enabling the heart to effectively pump blood throughout the body. Although the early postnatal period is widely recognized as a critical phase for cardiomyocyte maturation, the precise mechanisms initiating and orchestrating this process remain elusive. Using in vivo and in vitro models incorporated with multi-omic analyses, we here show that Mettl1 is a critical regulator in postnatal cardiomyocyte maturation. We demonstrate that Mettl1 is required for the proper ketogenesis in cardiomyocyte maturation via regulating Hmgcs2 translation. Loss of Mettl1 leads to aberrant metabolic reprogramming and subsequent cardiomyocyte immaturation through the deficiency in lysine β-hydroxybutyrylation of TCA cycle-related proteins. RNA-seq, Ribo-seq, and TRAC-seq were performed to identify differentially expressed genes, differentially translated genes and tRNA m7G methylome in 4-week-old Mettl1-cKO and control mouse hearts. RNA-seq was performed to identify differentially expressed genes in Mettl1-null and WT H9C2 cardiomyocytes.