Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters.
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.
Martino
Tami A
TA
University Health Network, Toronto, ON, Canada.
Oudit
Gavin Y
GY
Herzenberg
Andrew M
AM
Tata
Nazneen
N
Koletar
Margaret M
MM
Kabir
Golam M
GM
Belsham
Denise D
DD
Backx
Peter H
PH
Ralph
Martin R
MR
Sole
Michael J
MJ
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001831:Body Temperature / Q000502:physiology; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology*; D006224:Cricetinae; D004452:Echocardiography; D004591:Electrophoresis, Polyacrylamide Gel; D006339:Heart Rate / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000473:pathology / Q000648:ultrastructure; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D009043:Motor Activity / Q000502:physiology; D009206:Myocardium / Q000473:pathology; D040901:Proteomics; D013493:Suprachiasmatic Nucleus / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D016875:tau Proteins