Cardiac Sex Disparities are Established Prior to Gonad Formation

Sex disparities in cardiac homeostasis and heart disease are well documented with male-female differences attributed to actions of sex specific hormones. However, recent studies implied sex chromosomes might act outside of the gonads to function in non-hormonal manner. How these two pathways contribute to cardiac sex differences remains unknown. Here, we performed both transcriptional and proteomics profiling to define the molecular differences between male and female mouse hearts. We demonstrate that, contrary to current dogma, cardiac sex disparities are controlled not solely by sex hormones, but also through a sex chromosome mechanism. Using Turner syndrome (XO) and Klinefelter (XXY) mouse models, we find that the sex chromosome pathway is established by X-linked gene dosage. We also show that cardiac sex dipartites occur at the earliest stages of heart formation, a period before gonad formation. These studies provide new insights and resources for studying sex-biased cardiac disease states.