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 from 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 with XY-SryT (Sry deletion and overexpression of the Sry transgene in chromosome 3) and females with 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-mo-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-mo-old mice, soon after sexual maturation. The contribution of sex chromosomes (XX vs XY-Sry in mice with the same gonads and sex hormones) to several of our measurements becomes apparent in adult 4-mo-old mice. The contribution of 1X and 1Y-Sry vs 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 vs XY-Sry chromosome contribution to the musculoskeletal phenotype, which becomes more evident as the animals reach peak bone mass, suggesting that although gonadal sex has a major role, sex chromosomes are also an unrecognized contributor to musculoskeletal mass and bone strength.
Keywords: DXA; analysis/quantitation of bone; animal models; bone QCT/microCT; cell/tissue signaling - endocrine pathways; genetic animal models; sex steroids.
Sexual dimorphism, or the morphological differences between males and females, is often attributed to the hormones produced by the testes or ovaries. However, evidence suggests that sex chromosomes (XX or XY) also play a significant role. To separate the effects of these 2 factors on bone health, this work used a unique mouse model known as the Four-Core Genotypes (FCG). The FCG model allows us to manipulate the expression of the Sry gene, which determines testis development, resulting in 4 groups: XX mice with ovaries (XXO), XX mice with testes (XXT), XY mice with ovaries (XY-SryO), and XY mice with testes (XY-SryT). The results presented in this study revealed that the influence of sex chromosomes on the development of body weight, fat and lean/skeletal muscle mass, and bone mass becomes evident in an age-dependent manner, specifically after sexual maturity. Our evidence suggests that there are distinct differences in musculoskeletal development between mice with XX or XY chromosomes. We conclude that our findings uncovered sex chromosomes as a previously unacknowledged factor contributing to the sexual differences observed in musculoskeletal health.
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