The Core Circadian Clock Factor, Bmal1, Transduces Sex-specific Differences in Both Rhythmic and Nonrhythmic Gene Expression in the Mouse Heart

Sexual dimorphism in mammals, including humans and laboratory rodents, has primarily been attributed to hormonal and sex chromosomal differences. Accumulating evidence now suggests that circadian rhythms also contribute to sexual dimorphism in cardiac physiology and cardiovascular diseases. Here, we show that the circadian transcriptome of the mouse heart exhibits sexual dimorphism. We determined that female hearts express significantly more rhythmically expressed genes (REGs) and that the temporal distribution of the REGs was different between males and females. In addition, the overlap in genes and functional pathways were modest between males and females. All aspects of the sexual dimorphism in the circadian transcriptome was significantly diminished with cardiomyocyte specific loss of the core clock gene, Bmal1. Analysis of all differentially expressed genes (DEGs) between males and females showed that differential expression between sexes was largely diminished with loss of cardiomyocyte Bmal1. We conclude that cardiomyocyte specific Bmal1, and likely the core clock mechanism, plays a vital role in conferring a sexually dimorphic program of gene expression in the adult mouse heart. To investigate the role of BMAL1 in the sex differences of the heart circadian transcriptome in mice, we generated an inducible cardiomyocyte specific BMAL1 knockout (icsBmal1 KO) mouse.