Poster abstracts
Poster number 31 submitted by Jacob Longenecker
Heart-centric regulation of cellular and systemic metabolism by the m6A methyltransferase METTL3
Jacob Z. Longenecker (Department of Physiology and Cell Biology, College of Medicine, The Ohio State University; Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University), Jennifer M. Petrosino, Lisa E. Dorn, Federica Accornero
Abstract:
A critical and well-known characteristic of the heart is its ability to alter its metabolic activity in response to a variety of stressors, including variation of caloric availability and physical activity. Perturbation of this characteristic has been shown to have profound effects on cardiac function and importantly, systemic energy homeostasis. While most studies have focused on gene transcription, our laboratory has focused on post-transcriptional gene regulation and the study of N6-methyladenosine (m6A), the most abundant mRNA modification, in the heart. We have generated mouse models with heart-specific deletion or overexpression of methyltransferase-like 3 (METTL3), the enzyme responsible for the addition of m6A to mRNAs. We have found that in these mice, METTL3 deletion results in a significant decrease of cardiometabolic fitness at 8 months of age, as measured using exercise testing and represented as VO2 max. Strikingly, at 1 year of age mice lacking METTL3 in the heart become obese. A significant difference in total body weight, fat mass %, and lean mass % is not seen until after these mice have shown a cardiometabolic defect, indicating that a metabolic change in the heart precedes a systemic effect on these metrics. Our results suggest that this systemic change in metabolism is controlled via post-transcriptional modulation of heart-specific mRNAs, and provide a novel mechanism of heart-dependent regulation of obesity.
Keywords: Heart, METTL3, Metabolism