Document Detail


Development of dilated cardiomyopathy in Bmal1-deficient mice.
MedLine Citation:
PMID:  22707558     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Circadian rhythms are approximate 24-h oscillations in physiology and behavior. Circadian rhythm disruption has been associated with increased incidence of hypertension, coronary artery disease, dyslipidemia, and other cardiovascular pathologies in both humans and animal models. Mice lacking the core circadian clock gene, brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein (Bmal1), are behaviorally arrhythmic, die prematurely, and display a wide range of organ pathologies. However, data are lacking on the role of Bmal1 on the structural and functional integrity of cardiac muscle. In the present study, we demonstrate that Bmal1(-/-) mice develop dilated cardiomyopathy with age, characterized by thinning of the myocardial walls, dilation of the left ventricle, and decreased cardiac performance. Shortly after birth the Bmal1(-/-) mice exhibit a transient increase in myocardial weight, followed by regression and later onset of dilation and failure. Ex vivo working heart preparations revealed systolic ventricular dysfunction at the onset of dilation and failure, preceded by downregulation of both myosin heavy chain isoform mRNAs. We observed structural disorganization at the level of the sarcomere with a shift in titin isoform composition toward the stiffer N2B isoform. However, passive tension generation in single cardiomyocytes was not increased. Collectively, these findings suggest that the loss of the circadian clock gene, Bmal1, gives rise to the development of an age-associated dilated cardiomyopathy, which is associated with shifts in titin isoform composition, altered myosin heavy chain gene expression, and disruption of sarcomere structure.
Authors:
Mellani Lefta; Kenneth S Campbell; Han-Zhong Feng; Jian-Ping Jin; Karyn A Esser
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-15
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  303     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-16     Completed Date:  2012-10-26     Revised Date:  2013-08-18    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H475-85     Citation Subset:  IM    
Affiliation:
Center for Muscle Biology, University of Kentucky, Lexington, Kentucky 40536, USA.
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MeSH Terms
Descriptor/Qualifier:
ARNTL Transcription Factors / deficiency*,  genetics
Age Factors
Aging
Animals
Cardiomyopathy, Dilated / genetics,  metabolism*,  physiopathology,  ultrasonography
Disease Progression
Gene Expression Regulation
Heart Failure / metabolism,  physiopathology
Hypertrophy, Left Ventricular / metabolism,  physiopathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle Proteins / metabolism
Myocardial Contraction
Myocardium / metabolism*,  pathology
Myosin Heavy Chains / genetics,  metabolism
Protein Kinases / metabolism
RNA, Messenger / metabolism
Sarcomeres / metabolism,  pathology
Stroke Volume
Ventricular Dysfunction, Left / metabolism,  physiopathology
Ventricular Function, Left
Ventricular Pressure
Grant Support
ID/Acronym/Agency:
R01-AR-048816/AR/NIAMS NIH HHS; R01-AR-055246/AR/NIAMS NIH HHS; R01-HL-098945/HL/NHLBI NIH HHS; RC1ES018636/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/ARNTL Transcription Factors; 0/Arntl protein, mouse; 0/Muscle Proteins; 0/Myosin Heavy Chains; 0/RNA, Messenger; 0/connectin; EC 2.7.-/Protein Kinases
Comments/Corrections

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