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Disruption of the Circadian Clock within the Cardiomyocyte

ABSTRACT: Disruption of the Circadian Clock within the Cardiomyocyte Influences Myocardial Contractie Function, Metabolism, and Gene Expression Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally-based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We therefore generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse, in order to test this hypothesis. At 12 weeks of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80mmHg plus 1 microM epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase versus the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, while cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure, and modest mitochondrial dysfunction, in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression. Keywords: Comparison of circadian oscillations in gene expression in hearts taken from wildtype and transgenic animals

ORGANISM(S): Mus musculus

PROVIDER: GSE10045 | GEO | 2008/01/01

SECONDARY ACCESSION(S): PRJNA108617

REPOSITORIES: GEO

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Project description:Circadian clocks are cell autonomous timekeeping mechanisms that govern critical biological processes. Regarding the heart, the cardiomyocyte circadian clock regulates a diverse array of processes, ranging from transcription and translation, to signaling, metabolism, electrophysiology, and contractility. The importance of this mechanism is underscored by observations that genetic disruption of the cardiomyocyte circadian clock in murine models leads to adverse cardiac remodeling, heart failure, and reduced lifespan. However, the precise molecular links between the cardiomyocyte circadian clock and cardiac physiology/pathology have not been characterized fully. Given that recent studies have highlighted that small RNA species (such as miRNAs) influence both cardiac physiology and pathology, we sought to determine the extent to which cardiomyocyte circadian clock disruption impacts cardiac small RNA species. Accordingly, hearts were collected from cardiomyocyte-specific Bmal1 knockout (CBK) and littermate control (CON) mice at distinct times of the day. Small RNA-seq revealed 47 differentially expressed miRNA species in CBK hearts (in the absence of significant time-of-day-dependent effects). Subsequent bioinformatic analyses predicted that differentially expressed miRNA species in CBK hearts potentially influence processes such as circadian rhythmicity, cellular signaling, and metabolism. Of the induced miRNAs in CBK hearts, 7 were predicted to be targeted by the transcriptional repressors REV-ERB/ (integral circadian clock components that are directly regulated by BMAL1). Similar to CBK hearts, cardiomyocyte-specific Rev-erb/ double knockout (CM-RevDKO) mouse hearts exhibited increased let-7c-1-3p, miR-23b-5p, miR-139-3p, miR-5123, and miR-7068-3p levels. Importantly, 19 putative targets of these 5 miRNAs were commonly repressed in both CBK and CM-RevDKO heart (of which 16 are targeted by let-7c-1-3p). These observations suggest that disruption of the BMAL1–REV-ERB/ axis in the heart leads to induction of a subset of miRNAs, whose predicted mRNA targets have established functions in biological processes such as metabolism and cellular signaling.

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Disruption of the Circadian Clock within the Cardiomyocyte

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