Cardiomyocyte-Specific BMAL1 Plays Critical Roles in Metabolism, Signaling, and Maintenance of Contractile Function of the Heart

Abstract

Circadian clocks are cell autonomous, transcriptionally-based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a temporally appropriate manner. Critical to circadian clock function are two transcription factors, CLOCK and BMAL1. The purpose of the present study was to reveal novel physiologic functions of BMAL1 in the heart, as well as determine the pathologic consequences of chronic disruption of this circadian clock component. In order to address this goal, we generated cardiomyocyte-specific Bmal1 knockout (CBK) mice. Following validation of the CBK model, combined microarray and in silico analyses were performed, identifying 19 putative direct BMAL1 target genes, which included a number of metabolic (e.g., β-hydroxybutyrate dehydrogenase 1 [Bdh1]) and signaling (e.g., the p85α regulatory subunit of phosphatidylinositol 3-kinase [Pik3r1]) genes. Results from subsequent validation studies were consistent with regulation of Bdh1 and Pik3r1 by BMAL1, with predicted impairments in ketone body metabolism and signaling observed in CBK hearts. Furthermore, CBK hearts exhibited depressed glucose utilization, as well as a differential response to a physiologic metabolic stress (i.e., fasting). Consistent with BMAL1 influencing critical functions in the heart, echocardiographic, gravimetric, histologic, and molecular analyses revealed age-onset development of dilated cardiomyopathy in CBK mice, which was associated with a severe reduction in lifespan. Collectively, our studies reveal that BMAL1 influences metabolism, signaling, and contractile function of the heart.

Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation

“…Germline ablation of Bmal1 results in a premature aging phenotype, as described previously, suggesting a central role of Bmal1 in lifespan and survival. A recently published study shows that cardiomyocyte-specific Bmal1 deletion leads to development of dilated cardiomyopathy associated with reduced lifespan (42). The present study indicates that cardiac-specific deletion of Bmal1 leads to ventricular hypertrophy by the age of 28 wk and was initiated by a reparative form of fibrosis at 8 wk of age (triggered ECM response but not inflammatory response).…”

“…All animal procedures were conducted according to the "Guide for the Care and Use of Laboratory Animals" (8th ed., 2011) and were approved by the Institutional Animal Care and Use Committees at the University of Alabama at Birmingham. CBK (BMAL1 flox/flox /␣-MHC-CRE ϩ/Ϫ ) mice on the C57Bl/6J background were developed as previously described (12,42). Male CBK and C57BL/6J background littermate control mice (control) were maintained on a standard diet.…”

“…CBK mice have been reported to develop an age-dependent dilated cardiomyopathy (initially observed after 28 wk of age), with a shorter lifespan compared with control mice (42). To determine whether development of diastolic dysfunction occurred at a younger age in CBK mice, we measured diastolic function in CBK and control mice using Doppler echocardiography at 8 and 28 wk.…”

“…In humans, interrupted sleep duration, altered sleep-wake cycle, or insomnia directly associates with disturbed circadian rhythm and sudden sensorineural hearing loss marked with reduced levels of PER1 and CRY2 in peripheral leukocytes (41). In rodent hearts, the impact of disruption of two main transcription factors, CLOCK and BMAL1, has been investigated (42). These studies reveal important roles for these clock components in the heart at the levels of contractility, electrophysiology, metabolism, signaling, translation, and transcription (7).…”

“…Of these models, genetic ablation of BMAL1 in the heart elicits the most striking phenotype from 28 wk onwards: age-onset development of dilated cardiomyopathy associated with reduced life span. The mean survival for cardiomyocyte-specific Bmal1 deletion (CBK) mice was 33 wk, while no deaths were observed in littermate controls (i.e., Bmal1 flox/flox ) or wild-type (C57BL/6J) within one year of the study (42).…”