mA epitranscriptomic regulation of tissue homeostasis during primate aging

How N-methyladenosine (mA), the most abundant mRNA modification, contributes to primate tissue homeostasis and physiological aging remains elusive. Here, we characterize the mA epitranscriptome across the liver, heart and skeletal muscle in young and old nonhuman primates. Our data reveal a positive correlation between mA modifications and gene expression homeostasis across tissues as well as tissue-type-specific aging-associated mA dynamics. Among these tissues, skeletal muscle is the most susceptible to mA loss in aging and shows a reduction in the mA methyltransferase METTL3. We further show that METTL3 deficiency in human pluripotent stem cell-derived myotubes leads to senescence and apoptosis, and identify NPNT as a key element downstream of METTL3 involved in myotube homeostasis, whose expression and mA levels are both decreased in senescent myotubes. Our study provides a resource for elucidating mA-mediated mechanisms of tissue aging and reveals a METTL3-mA-NPNT axis counteracting aging-associated skeletal muscle degeneration.