Development of dilated cardiomyopathy inBmal1-deficient mice

Abstract

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.

The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility

“…Recent work from our laboratory demonstrated the presence of dilated cardiomyopathy in the germline Bmal1 knockout mouse (32). These mice also demonstrated increased stretch-induced arrhythmia before any overt structural changes were observed (unpublished observations).…”

“…Sophisticated studies using the circadian reporter mouse in which luciferase is knocked into the Per2 locus (mPER2:LUC) have allowed investigators to use bioluminescence recording in cell and tissue explants ex vivo to demonstrate that the circadian clocks in peripheral tissues are selfsustaining and can function in a cell-autonomous manner. While the circadian clock has been shown to exist in the heart and other peripheral tissues, we are only just learning what role it plays in cellular function.Studies in mice and hamsters in which the circadian clocks, in all tissues, are disrupted have provided important data suggesting links between disruption of the molecular clock and cardiac pathology with end points including altered systolic ventricular function, cardiac hypertrophy, and arrhythmogenic events (28,32,36,37). These studies, however, do not distinguish between the role of the clock mechanism in the heart versus the disruption of the central clock.…”

“…Studies in mice and hamsters in which the circadian clocks, in all tissues, are disrupted have provided important data suggesting links between disruption of the molecular clock and cardiac pathology with end points including altered systolic ventricular function, cardiac hypertrophy, and arrhythmogenic events (28,32,36,37). These studies, however, do not distinguish between the role of the clock mechanism in the heart versus the disruption of the central clock.…”

Mechanism of the circadian clock in physiology

“…Klf15 is a transcription factor that regulates expression of potassium channels that are responsible for the generation of polarization. Further evidence for the importance of the clock in the heart comes from a recent study showing that BMAL1 KO mice develop dilated cardiomyopathy with age, in which the heart becomes weakened and enlarged, resulting in decreased cardiac output (73).…”

Circadian rhythm and cardiovascular disorders

“…95 In addition, Lefta et al showed subtle shifts in titin isoform composition, altered myosin heavy chain gene expression at the mRNA level, and disruption of sarcomere structure in BMAL1 null hearts, although passive tension in single cardiomyocytes was unaltered. 96 These studies suggest a possible role for the molecular clock in regulating the passive properties and structure of sarcomeres in addition to their active contractile properties, but more definitive studies are needed.…”