Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation

Sex disparities in cardiac homeostasis and heart disease are well documented, with differences attributed to actions of sex hormones. However, studies have indicated sex chromosomes act outside of the gonads to function without mediation by gonadal hormones. Here, we performed transcriptional and proteomics profiling to define differences between male and female mouse hearts. We demonstrate, contrary to current dogma, cardiac sex disparities are controlled not only by sex hormones but also through a sex-chromosome mechanism. Using Turner syndrome (XO) and Klinefelter (XXY) models, we find the sex-chromosome pathway is established by X-linked gene dosage. We demonstrate cardiac sex disparities occur at the earliest stages of heart formation, a period before gonad formation. Using these datasets, we identify and define a role for alpha-1B-glycoprotein (A1BG), showing loss of A1BG leads to cardiac defects in females, but not males. These studies provide resources for studying sex-biased cardiac disease states. [Display omitted] •Sex hormones and sex-chromosome mechanisms contribute to cardiac sex disparities•Sex-chromosome pathway in the heart is established by X-linked gene dosage•Cardiac sex disparities occur before sex gonad formation•Loss of A1BG leads to cardiac defects in females, but not in males Male/female differences in cardiac function and disease have been attributed to hormonal differences. In this paper, though transcriptomic and proteomic analyses in mice, Shi et al. find that cardiac differences first appear in embryos prior to gonad formation, suggesting a sex-chromosome-dependent mechanism.