Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression

Abstract

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 to test this hypothesis. At 12 wk 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 (80 mmHg plus 1 M epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase vs. the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, whereas 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.

Circadian clocks: from stem cells to tissue homeostasis and regeneration

“…Mining this database can help to understand or explain tissue‐specific circadian physiology. For instance, CCGs in the murine heart are involved in cardiac glucose and fatty acid metabolism (e.g., Dgat2 , Adpn , Ppp1cc 32), but also electrophysiology which results in oscillatory contractile properties 33 (e.g., Tcap 34 , Kv4.2, and KChIP2 35). Surprisingly, the cardiac‐specific clock not only drives rhythmic output under normal physiological conditions, but also under pathophysiological conditions as noted by its oscillating responsiveness to myocardial infarction mediated by oscillating phosphorylated Akt and GSK‐3 levels 36.…”

A Time to Fast, a Time to Feast: The Crosstalk between Metabolism and the Circadian Clock

“…A possible risk factor for cardiovascular disease is a circadian dysfunction of the heart, where CLOCK regulates myocardial oleate oxidation and oxygen consumption by activation of fatty acid transport protein 1 (päÅOT~N) as well as of the a3 and b3 subunits of NADH hydrogenase (kÇìÑ~PLÄP) (Bray=et alK, 2008). Furthermore, metabolic processes unrelated to energy balance have been reported to be regulated by the circadian clock.…”

On Circadian Variation of Myocardial Reperfusion Injury

“…Cardiomyocytespecific circadian clock mutant (CCM) mice, in which the circadian clock has been selectively disrupted, have provided important information on the function of these genes. 6 In 1985, in an analysis of the Multicenter Analysis of the Limitations of Infarct Size, Muller et al 7 observed a marked circadian periodicity in the time of onset of the clinical manifestations of acute myocardial infarction, with a peak incidence between 6 AM and noon. This increased morning incidence has been confirmed repeatedly in individual populations and in a meta-analysis of more than 60 000 patients.…”