Sex chromosome and gonadal contributions to body composition and skeletal mass and strength in aged four core genotypes (FCG) mice

Sex differences in musculoskeletal aging are often attributed to gonadal hormones, but the independent role of sex chromosomes remains unclear. Using the Four Core Genotype mouse model, which dissociates sex chromosomes (XX vs. XY) from gonadal sex (ovaries vs. testes), our goal was to examine sex chromosomes and gonads independent and interactive effects on bone, muscle and organ phenotypes from 8 to 20 months of age in XXO, XYO, XXT, and XYT mice. XYO mice showed high mortality (38.7%-survival by 20 months) when compared with other genotypes (67-86.7%). Between 8 and 20 months, XYO mice showed increases in lean mass and femoral BMD and improved bone structural parameters, yet lower cortical tissue mineral density. XXO mice displayed pronounced late-life gains in body weight, lean and fat mass not observed in other genotypes, although lean mass differed only versus XXT mice at 20 months. Total and spine BMD declined in XXO mice, accompanied with lower structural parameters and higher tissue mineral density than XYO mice. XXT mice displayed bone loss at all skeletal sites, whereas XYT mice showed a selective decline in spine BMD. Overall, chromosome sex adversely affected bone and muscle mass in XX versus XY mice, while gonadal sex influenced bone structure and absolute muscle mass, with mice bearing ovaries generally exhibiting lower muscle mass. Organ weight effects were modest and limited to spleen (XYO > XXO/XYT) and brain (XYT > XXT). Collectively, these findings reveal a previously unrecognized, tissue-specific contribution of sex chromosomes to musculoskeletal aging, independent of gonadal sex.