Abstract
BackgroundThe C57BL/6J.YA/J mouse strain is a chromosome-substituted line where the original male-specific portion of chromosome Y (MSY) from C57BL/6J mice was substituted for that from A/J mice. In hearts from male C57BL/6J.YA/J and C57BL/6J mice, orchidectomy (ORX) affected in a strictly strain-specific fashion the expression a subset of genes showing enrichment for functional categories, including that of circadian rhythms and cardiac contractility. We further tested whether: (1) there were strain-specific differences in cardiac circadian rhythms; (2) strain-dependent differences in the effects of ORX on contractility genes translated into differences in cardiac functions; and (3) differential contractility responses occurred preferentially at times when circadian rhythms also showed strain-specific differences.MethodsIn hearts from the two above strains, we (1) profiled the expression levels of 15 circadian genes at 4-h intervals across a 24 h period; (2) tested the effects of either ORX or androgen replacement on expression of cardiac contractility genes, and that of ORX on myocardial functional reserve; and (3) verified whether the effects of MSY variants on cardiac contractility-related responses showed synchronicity with differences in circadian rhythms.ResultsAmong the 15 tested circadian genes, a subset of them were affected by strain (and thus the genetic origin of MSY), which interacted with the amplitude of their peak of maximal expression at 2:00 PM. At that same time-point, ORX decreased (and androgen supplementation increased) the expression of three contractility-related genes, and decreased myocardial relaxation reserve in C57BL/6J.YA/J, but not in C57BL/6J mice. These effects were not detected at 10:00 AM, i.e., at another time-point when circadian genes showed no strain-specific differences.ConclusionsThe results indicate that in mice, androgens have activational effects on cardiac circadian rhythms, contractile gene expression, and myocardial functional reserve. All effects occurred preferentially at the same time of the day, but varied as a function of the genetic origin of MSY. Androgens may therefore be necessary but not sufficient to impart male-specific characteristics to some particular cardiac functions, with genetic material from MSY being one other necessary factor to fully define their range of actions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0116-4) contains supplementary material, which is available to authorized users.
Highlights
The C57BL/6J.YA/J mouse strain is a chromosome-substituted line where the original male-specific portion of chromosome Y (MSY) from C57BL/6J mice was substituted for that from A/J mice
Our comparative studies revealed that (1) cardiomyocytes from adult C57BL/6 J.YA/J/NaJ hearts were smaller than that from their C57BL/6 J counterparts [14]; (2) orchidectomy (ORX) decreased the size of cardiomyocytes from adult C57BL/6J mice, but not that from their C57BL/6 J.YA/J/NaJ counterparts; and (3) Orchidectomy or orchidectomized (ORX) decreased in adult male C57BL/6 J.YA/J/Naj mice the expression of phospholamban (Pln), titin (Ttn) and “four and a half LIM domains 2” (Fhl2), i.e., three genes closely related to cardiac contractility, relaxation, and performance [6]
We found that the effects of MSY variants on cardiac expression of contractility genes were accompanied by differences in myocardial functional reserve, with all effects occurring preferentially at time-points when circadian genes showed strainspecific differences
Summary
The C57BL/6J.YA/J mouse strain is a chromosome-substituted line where the original male-specific portion of chromosome Y (MSY) from C57BL/6J mice was substituted for that from A/J mice. Androgens are responsible for many aspects of male differentiation and keep contributing after puberty to many male-specific phenotypes [1, 2], there is emerging evidence that MSY has actions that can be distinguished from that of gonadal steroids [3]. Another manner whereby MSY may affect male-specific characteristics is (as shown previously in rats [4] or mice [5, 6]) via modulation of the effects of androgens, and by a mechanism that involves combined actions of both gonadal and chromosomal sex. Our comparative studies revealed that (1) cardiomyocytes from adult C57BL/6 J.YA/J/NaJ hearts were smaller than that from their C57BL/6 J counterparts [14]; (2) orchidectomy (ORX) decreased the size of cardiomyocytes from adult C57BL/6J mice, but not that from their C57BL/6 J.YA/J/NaJ counterparts; and (3) ORX decreased in adult male C57BL/6 J.YA/J/Naj mice (but not in their C57BL/6J counterparts) the expression of phospholamban (Pln), titin (Ttn) and “four and a half LIM domains 2” (Fhl2), i.e., three genes closely related to cardiac contractility, relaxation, and performance [6]
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