Female Clock Δ19/Δ19 mice are protected from the development of age-dependent cardiomyopathy

Abstract

Aims Circadian rhythms are important for healthy cardiovascular physiology and they are regulated by the molecular circadian mechanism. Previously, we showed that disruption of the circadian mechanism factor CLOCK in male Clock δ19/δ19 mice led to development of age-dependent cardiomyopathy. Here, we investigate the role of biological sex in protecting against heart disease in aging female Clock δ19/δ19 mice. Methods and Results Female Clock δ19/δ19 mice are protected from the development of cardiomyopathy with age, as heart structure and function are similar to 18 months of age vs. female WT mice. We show that female Clock δ19/δ19 mice maintain normal glucose tolerance as compared with female WT. Tissue metabolic profiling revealed that aging female Clock δ19/δ19 mice maintain normal cardiac glucose uptake, whereas the male Clock δ19/δ19 mice have increased cardiac glucose uptake consistent with pathological remodelling. Shotgun lipidomics revealed differences in phospholipids that were sex and genotype specific, including cardiolipin CL76:11 that was increased and CL72:8 that was decreased in male Clock δ19/δ19 mice. Additionally, female Clock δ19/δ19 mice show increased activation of AKT signaling and preserved cytochrome c oxidase activity compared with male Clock δ19/δ19 mice, which can help to explain why they are protected from heart disease. To determine how this protection occurs in females even with the Clock mutation, we examined the effects of ovarian hormones. We show that ovarian hormones protect female Clock δ19/δ19 mice from heart disease as ovariectomized female Clock δ19/δ19 mice develop cardiac dilation, glucose intolerance and reduced cardiac cytochrome c oxidase; this phenotype is consistent with the agedependent decline observed in male Clock δ19/δ19 mice. Conclusions These data demonstrate that ovarian hormones protect female Clock δ19/δ19 mice from the development of agedependent cardiomyopathy even though Clock function is disturbed. Understanding the interaction of biological sex and the circadian mechanism in cardiac growth, renewal and remodelling opens new doors for understanding and treating heart disease.