Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters

TLDR

Sleep deprivation, shift work, and jet lag disrupt biological rhythms and harm health, yet circadian disorganization had not previously been proven a causal risk factor for organ disease. The point mutation in casein kinase‑1ε causes early circadian entrainment and fragmented behavioral patterns in +/tau heterozygous hamsters. Animals with the tau mutation die young from cardiomyopathy, fibrosis, impaired contractility, and severe renal disease, but aligning light cycles to their 22‑h rhythm normalizes behavior and reverses the cardiorenal pathology, and SCN ablation prevents hypertrophy, demonstrating that circadian organization is essential for health and longevity and that chronic asynchrony drives cardiac and renal disease.

Abstract

Sleep deprivation, shift work, and jet lag all disrupt normal biological rhythms and have major impacts on health; however, circadian disorganization has never been shown as a causal risk factor in organ disease. We now demonstrate devastating effects of rhythm disorganization on cardiovascular and renal integrity and that interventions based on circadian principles prevent disease pathology caused by a short-period mutation (tau) of the circadian system in hamsters. The point mutation in the circadian regulatory gene, casein kinase-1epsilon, produces early onset circadian entrainment with fragmented patterns of behavior in +/tau heterozygotes. Animals die at a younger age with cardiomyopathy, extensive fibrosis, and severely impaired contractility; they also have severe renal disease with proteinuria, tubular dilation, and cellular apoptosis. On light cycles appropriate for their genotype (22 h), cyclic behavioral patterns are normalized, cardiorenal phenotype is reversed, and hearts and kidneys show normal structure and function. Moreover, hypertrophy does not develop in animals whose suprachiasmatic nucleus was ablated as young adults. Circadian organization therefore is critical for normal health and longevity, whereas chronic global asynchrony is implicated in the etiology of cardiac and renal disease.