Abstract Vertebrate sexual dimorphism is ascribed to the presence of testes or ovaries, and, hence, to the secretion of gonad-specific hormones. However, mounting evidence indicates that sex differences in tissues and organs also stem from the presence of sex chromosomes (XX or XY). To tease out the contribution of gonads from sex chromosomes to the musculoskeletal system, we used the Four-Core Genotypes (FCG) mouse model, in which the Sry gene, which dictates testis formation, was either deleted in the Y chromosome, resulting in XY mice with ovaries (XY-SryO), or overexpressed in XX mice, resulting in XX mice with testes (XXT), together with gonadal males XY-SryT (Sry deletion and overexpression of the Sry transgene in chromosome 3) and females XXO. The FCG mice are generated by crossing XXO with XY-SryT mice, all of C57BL/6 J background. We now show that the musculoskeletal phenotype of 2- to 4-month-old FCG mice varies based on both gonads and sex chromosomes, depending on the age and the organ/tissue/cell analyzed. The effect of sex chromosomes on body weight, fat and lean/skeletal muscle mass, and bone mass and structure is minor in 2-/3-month-old mice, soon after sexual maturation. The contribution of sex chromosomes (XX versus XY-Sry in mice with the same gonads and sex hormones) in several of our measurements becomes apparent in adult 4-month-old mice. Contribution of 1X and 1Y-Sry versus 2X chromosomes varies among different measurements in gonadal males or females, and mice with XY-Sry chromosomes might have higher or lower values that XX mice. Our study shows XX versus XY-Sry chromosome contribution to the musculoskeletal phenotype, which becomes more evident as the animals reach peak bone mass, suggesting that while gonadal sex has a major role, sex chromosomes are a so far unrecognized contributor to musculoskeletal mass and bone strength.

Independent contribution of gonads and sex chromosomes to sex differences in bone mass and strength in the four-Core genotypes mouse model