Chromosome Y variants from different inbred mouse strains are linked to differences in the morphologic and molecular responses of cardiac cells to postpubertal testosterone

Background: We have reported previously that when chromosome Y (chrY) from the mouse strain C57BL/6J (ChrY(C57)) was substituted for that of A/J mice (ChrY(A)), cardiomyocytes from the resulting chromosome substitution C57BL/6J-chrY(A) strain were smaller than that of their C57BL/6J counterparts. In reverse, when chrY(A) from A/J mice was substituted for that of chrY(C57), cardiomyocytes from the resulting A/J-chrY(C57) strain were larger than in their A/J counterparts. We further used these strains to test whether: 1) the origin of chrY could also be linked to differences in the profile of gene expression in the hearts of adult male mice, and 2) post-pubertal testosterone could play a role in the differential morphologic and/or molecular effects of chrY(C57) and chrY(A). Results: The increased size of cardiomyocytes from adult male C57BL/6J mice compared to C57BL/6J-chrY(A) resulted from the absence of hypertrophic effects of post-pubertal testosterone on cells from the latter strain. However, gene profiling revealed that the latter effect could not be explained on the basis of an insensitivity of cells from C57BL/6J-chrY(A) to androgens, since even more cardiac genes were affected by post-pubertal testosterone in C57BL/6J-chrY(A) hearts than in C57BL/6J. By testing for interaction between the effects of surgery and strain, we identified 249 interaction genes whose expression was affected by post-pubertal testosterone differentially according to the genetic origin of chrY. These interaction genes were found to be enriched within a limited number of signaling pathways, including: 1) p53 signaling, which comprises the interacting genes Ccnd1, Pten and Cdkn1a that are also potential co-regulators of the androgen receptors, and 2) circadian rhythm, which comprises Arntl/Bmal1, which may in turn regulate cell growth via the control of Cdkn1a. Conclusion: Although post-pubertal testosterone increased the size of cardiomyocytes from male C56BL/6J mice but not that from their C57BL/6J-chrY(A) counterparts, it affected gene expression in the hearts from both strains. However, several cardiac genes responded to post-pubertal testosterone in a strict strain-selective manner, which provides possible mechanisms explaining how chrY may, in part via interference with androgen regulatory events, be linked to morphologic differences of cardiac cells of adult male mice.