Cardiac-Specific Mutation of Clock Alters the Quantitative Measurements of Physical Activities without Changing Behavioral Circadian Rhythms

Abstract

Even though peripheral circadian oscillators in the cardiovascular system are known to exist, the daily rhythms of the cardiovascular system are mainly attributed to autonomic or hormonal inputs under the control of the central oscillator, the suprachiasmatic nucleus (SCN). In order to examine the role of peripheral oscillators in the cardiovascular system, we used a transgenic mouse where the Clock gene is specifically disrupted in cardiomyocytes. In this cardiomyocyte-specific CLOCK mutant (CCM) mouse model, the circadian input from the SCN remains intact. Both CCM and wild-type (WT) littermates displayed circadian rhythms in wheel-running behavior. However, the overall wheel-running activities were significantly lower in CCM mice compared to WT over the course of 5 weeks, indicating that CCM mice either have lower baseline physical activities or they have lower physical adaptation abilities because daily wheel running, like routine exercise, induces physical adaptation over a period of time. Upon further biochemical analysis, it was revealed that the diurnal oscillations of phosphorylation states of several kinases and protein expression of the L-type voltage-gated calcium channel (L-VGCC) α1D subunit found in WT hearts were abolished in CCM hearts, indicating that in mammalian hearts, the daily oscillations of the activities of these kinases and L-VGCCs were downstream elements of the cardiac core oscillators. However, the phosphorylation of p38 MAPK exhibited robust diurnal rhythms in both WT and CCM hearts, indicating that cardiac p38 could be under the influence of the central clock through neurohormonal signals or be part of the circadian input pathway in cardiomyocytes. Taken together, these results indicate that the cardiac core oscillators have an impact in regulating circadian rhythmicities and cardiac function.

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

“…, the p85α subunit of PI3K). We have previously reported that the phosphorylation status of two kinases that are downstream of PI3K (namely AKT and GSK3β) appear to be under circadian clock control (as evidenced by loss of time-of-dependent oscillations in CCM hearts) (Durgan et al 2010; Ko, et al 2011); similar findings regarding clock regulation of AKT phosphorylation have been reported in extra cardiac tissues, using germline Bmal1 null and Per2 mutant mice (Anea, et al 2009; Carvas, et al 2012). Consistent with impaired PI3K activity, both AKT and GSK3β phosphorylation were attenuated in CBK hearts (Figure 4E).…”

Myeloid Cell-specific Disruption of Period1 and Period2 Exacerbates Diet-induced Inflammation and Insulin Resistance

“…After the feeding regimen mPer2 Luc mice were subjected to the same assays used for C57BL/6J mice. Additionally, both HFD-fed and LFD-fed mPer2 Luc mice were subjected to examination of wheel-running locomotor activity rhythms as previously described (40). Some age-matched female mPer2…”

“…For both cell types, the medium was changed ϳ24 h after plating so as to reduce the FBS concentration to 5%, and about 12 h later cultures were exposed to medium containing 50% adult horse serum for 2 h. Thereafter, serum-shocked SVC and BMDM were maintained in serumfree recording medium containing 0.1 mM beetle luciferin (Promega), 25 units/ml penicillin, and 25 g/ml streptomycin for bioluminescence analysis as described previously (40). Individual cultures were sealed airtight with sterile glass coverslips (VWR) and sterile silicon grease (Dow Corning).…”

Consequences of Circadian and Sleep Disturbances for the Cardiovascular System

“…Time-of day dependent oscillations have been reported in the heart for the voltage dependent potassium channels K v 1.5 and K v 4.2 158 , and the L-type voltage-gated calcium channel subunit VGCCα1D. 159 Also, L-type calcium channel current densities increase during the active period which is consistent with the nocturnal elevation in murine heart rate. 155,157 Moreover, circadian variations in potassium channel interacting protein-2 (KChIP2) affect potassium channel opening in a manner that is consistent with changes in action potential duration and circadian variations in heart rate.…”