Mechanism(s) for age-related sex differences in diet-induced cardiomyopathy: role of RNA methylation

Abstract Background/Introduction Age and sexual dimorphism contribute to the differential cardiometabolic dysfunctions associated with diet-induced obesity. However, underlying mechanisms remain elusive. RNA modifications via m6A methylation, is an emerging mediator of stability, translation localization responsible for regulation multiple biological functions. are regulated by “writers”, “erasers” “readers”. The role methylation machinery genes in heart largely unexplored, may provide insight into influence age sex on dysfunction. Purpose We aim determine changes within a cardiomyopathy mouse model, stratified according sex. Methods Male female C57BL/6 mice (6–8wk-old) were fed normal chow (NC) or high-fat/high-sucrose (HFHS) diet 1 4 months. Echocardiographic measurements performed at months American Society Echocardiography European Association Cardiovascular Imaging guidelines. At study endpoint, glucose insulin tolerance testing was conducted injecting intraperitoneally 2g/kg 0.6U/kg insulin, monitoring blood levels over 2 hour period. from tissue subjected quantitative PCR (FTO, ALKBH5, METTL3, METTL4, METTL14, YTHDF1 YTHDF2). PPIA used normalise qPCR data. Results Both male showed evidence age- metabolic dysfunction, however, males females markedly different impairments. For example, exacerbated HFHS but not females; only impaired tolerance. that had systolic (stoke volume, cardiac output) diastolic (E/A ratio) dysfunction after diet, while unperturbed. identified METTL3 “writers” consistently increased hearts vs unchanged decreased females, irrespective diet. Conversely, YTHDF1, “reader”, vs. significantly hearts. Conclusion Our confirms impairments occur versus response long-term Despite significant impairment both sexes, evident males. differentially expressed sex, suggesting be involved age-related Funding Acknowledgement Type funding sources: Foundation. Main source(s): Heart Foundation