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Cardiovascular Research Advance Access originally published online on February 26, 2008
Cardiovascular Research 2008 79(2):228-237; doi:10.1093/cvr/cvn054
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Diurnal variations in myocardial metabolism

Molly S. Bray and Martin E. Young*

USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030, USA

* Corresponding author. Tel: +1 713 798 7567; fax: +1 713 798 7101. E-mail address: meyoung{at}bcm.edu

Received 6 December 2007; revised 20 February 2008; accepted 22 February 2008

Time for primary review: 21 days


   Abstract
Top
 Abstract
1. Introduction
 2. Diurnal variations in...
 3. Potential mechanisms...
 4. Potential mechanistic links...
 5. Interrelationship between...
 6. Summary
 Funding
 References
 
The heart is challenged by a plethora of extracellular stimuli over the course of a normal day, each of which distinctly influences myocardial contractile function. It is therefore not surprising that myocardial metabolism also oscillates in a time-of-day dependent manner. What is becoming increasingly apparent is that the heart exhibits diurnal variations in its intrinsic properties, including responsiveness to extracellular stimuli. This article summarizes our current knowledge regarding the mechanism(s) mediating diurnal variations in myocardial metabolism. Particular attention is focused towards the intramyocardial circadian clock, a cell autonomous molecular mechanism that appears to regulate myocardial metabolism both directly (e.g. triglyceride and glycogen metabolism) and indirectly (through modulation of the responsiveness of the myocardium to workload, insulin, and fatty acids). In doing so, the circadian clock within the cardiomyocyte allows the heart to anticipate environmental stimuli (such as changes in workload, feeding status) prior to their onset. This synchronization between the myocardium and its environment is enhanced by regular feeding schedules. Conversely, loss of synchronization may occur through disruption of the circadian clock and/or diurnal variations in neurohumoral factors (as observed during diabetes mellitus). Here, we discuss the possibility that loss of synchronization between the heart and its environment predisposes the heart to metabolic maladaptation and subsequent myocardial contractile dysfunction.

KEYWORDS Chronobiology; Circadian clock; Fatty acids; Glucose; Heart


   1. Introduction
Top
 Abstract
 1. Introduction
2. Diurnal variations in...
 3. Potential mechanisms...
 4. Potential mechanistic links...
 5. Interrelationship between...
 6. Summary
 Funding
 References
 
Organisms are subjected to dramatic environmental fluctuations, such as light, temperature, nutrients (both macro and micro), water, humidity, noise, predation, toxins, and pathogens. Despite these environmental fluctuations, multiple biological processes must be maintained within physiologic boundaries. Failure to achieve a specific level of homeostasis results in pathogenesis. The majority of environmental factors oscillate in a somewhat predictable manner, depending on both the time of day (i.e. circadian) and year (i.e. seasonal). It is therefore not surprising that virtually every organism has evolved mechanisms for perception of the time of day and season, which in turn directly modulate specific biological processes. Given obvious seasonal-dependent alterations in a number of time-of-day dependent environmental factors (e.g. light/dark cycles), it is not surprising that considerable overlap exists between seasonal and circadian ‘time-keepers’. Undoubtedly, the primary timekeeping mechanism in mammals is the intracellular circadian clock.1–4

Circadian clocks can be defined as transcriptionally-based positive and negative feedback loops with a free running period of ~24 h.1 This is a cell autonomous molecular mechanism, persisting in both tissue and cell culture.5–8 Circadian clocks have been found in virtually every mammalian cell type investigated to date. At the core of mammalian circadian clock mechanism lie two critical transcription factors, CLOCK and BMAL1.9,10 Upon heterodimerization, CLOCK/BMAL1 induce components of the positive (e.g. BMAL1 itself) and negative (e.g. PER1/2/3, CRY1/2, REV-ERBA{alpha}, DEC1/2) loops; the latter repress transcriptional activity of the CLOCK/BMAL1 heterodimer.11–14 The CLOCK/BMAL1 heterodimer also induces a number of genes not involved in the core clock mechanism, known as clock output genes, many of which are themselves transcription factors (e.g. DBP), capable of influencing expression of a plethora of target genes.15 Similarly, components of the negative loops (e.g. REV-ERBA{alpha}) mediate functional output from the clock mechanism (i.e. influence expression of non-core clock genes).16 Through modulating expression of output genes, the circadian clock is able to alter cellular function over the course of the day. The mammalian circadian clock mechanism has been reviewed in greater detail elsewhere.1,17,18

The circadian clock mechanism provides the selective advantage of anticipation, enabling the cell to perceive the time of day. In doing so, circadian clocks facilitate cellular responses to environmental stimuli in both a rapid and temporally appropriate manner. Although specific environmental factors display highly predictable circadian rhythms (e.g. light/dark cycles), others are somewhat less predictable (e.g. feeding/fasting cycles). In addition, specific environmental factors displaying circadian rhythms may require opposing cellular responses. For example, increased physical activity upon awakening would activate catabolic processes, while feeding upon awakening would require activation of anabolic processes. A high degree of plasticity must remain inherent within this system (i.e. circadian clocks can influence cellular processes without committing the cell to a specific cellular function). Given continuous fluctuations in the environment, it is imperative that circadian clocks be exquisitely sensitive to environmental cues (e.g. alterations in the light/dark cycle when travelling through time zones), thereby maintaining a selective advantage. In addition, during many disease states (e.g. diabetes mellitus, hypertension), neuronhumoral circadian rhythms are impaired in a chronic fashion, in turn causing a dyssynchrony between cells with their internal and external environments.19

The circadian clock mechanism has recently been exposed within cardiomyocytes, facilitating development of novel hypotheses with respect to mediators of known circadian rhythmicities in cardiac physiology (e.g. heart rate, cardiac output) and pathophysiology (e.g. arrthymias).6,17 The purpose of this article is to review our current understanding of the role(s) of the cardiomyocyte circadian clock, with particular focus on myocardial metabolism. The two most physiologically relevant environmental circadian cycles influencing myocardial function are sleep/wake and feeding/fasting cycles. These will therefore be utilized as recurring examples of environmental factors for which myocardial anticipation has a critical functional consequence.


   2. Diurnal variations in myocardial metabolism of the rat
Top
 Abstract
 1. Introduction
 2. Diurnal variations in...
3. Potential mechanisms...
 4. Potential mechanistic links...
 5. Interrelationship between...
 6. Summary
 Funding
 References
 
Myocardial metabolism and contractile function are closely interlinked.20 Periods of workload-induced elevation of energy demand are matched by increased rates of oxidative and non-oxidative substrate utilization.21 Conversely, abnormalities in myocardial metabolism (e.g. fatty acid β-oxidation defects) that limit ATP generation, in turn, adversely affect myocardial contractile function and survival of the organism.22,23 Myocardial metabolism is therefore a highly dynamic entity, capable of adapting to environmental stimuli in a rapid manner. Myocardial metabolism is also modulated during relatively prolonged physiologic and pathophysiologic periods, such as developmental transitions (e.g. foetal to adult) and disease states (e.g. heart failure).24–26 Collectively, improved understanding of the molecular mechanisms governing myocardial metabolism will provide novel insight into both cardiac physiology and pathology.

Over the course of a 24 h period, sleep/wake and feeding/fasting cycles markedly influence the myocardium. Periods of wakefulness are associated with increased physical activity, heart rate, and cardiac output.27,28 For healthy mammals dwelling in an environment of ample food availability (e.g. ad libitum fed laboratory rodents, humans in Western society), periods of wakefulness are typically associated with increased food consumption. However, animals within that natural habitate (including humans prior to Westernization) are not guaranteed success in their forage for food. Prolongation of the sleep-phase fast may therefore occur, lasting up to several days/weeks, depending upon the organism, season, and environment. Two primary scenarios are therefore possible, both of which are evolutionarily advantageous to anticipate. These are the successful and unsuccessful foraging for food upon awakening. Upon awakening, increased physical activity and myocardial function will rely upon increased ATP generation through metabolism of both exogenous (e.g. plasma glucose, lactate, and fatty acids) and endogenous (e.g. intracellular glycogen and triglyceride) substrates. When the sleep-phase fast ends, the heart needs to efficiently replenish endogenous energy stores, such as glycogen and triglyceride, which were utilized between feeding bouts. In contrast, if the animal is unsuccessful in its forage during the awake phase, peripheral tissues (such as the heart) need to decrease glucose uptake and utilization, instead increasing reliance on circulating fatty acids and endogenous stores as substrates for ATP generation. It is therefore advantageous for the heart to anticipate increased contractility, prolongation of the sleep-phase fast, and successful foraging for food during the awake phase. Since each of these situations has distinct (often opposing) metabolic signals and requirements, it is not readily apparent if, or how, this might be possible. The question regarding ‘if’ will be addressed first.

Studies investigating diurnal variations in metabolism have focused primarily at the whole body level and/or on the liver.29–32 Our knowledge of diurnal variations in myocardial metabolism remains in its infancy. The vast majority of studies investigating time-of-day dependent oscillations in myocardial metabolism have utilized rodent models. Marked diurnal variations in oxidative and non-oxidative glucose and fatty acid metabolism have been observed in the rat heart (Figure 1). Early reports revealed diurnal variations in myocardial glycogen content that mirror feeding/fasting cycles in the ad libitum fed rat, peaking at the end of the awake phase.33 As such, these observations are classically attributed to feeding-dependent diurnal variations in circulating nutrients (e.g. glucose) and hormones (e.g. insulin). However, numerous observations suggest that additional mechanisms likely mediate diurnal variations in tissue glycogen levels. The most striking includes persistence of diurnal variations in hepatic glycogen content during prolonged fasting.34 Although similar diurnal studies have not been performed for the heart, it is appreciated that myocardial glycogen levels do not behave as one might anticipate if regulated solely by feeding-dependent humoral factors. For example, myocardial glycogen content increases during acute fasting.35 As with myocardial glycogen content, myocardial triglyceride content exhibits diurnal variations in the rat, although levels of this endogenous energy store peak at the sleep-to-wake transition.36 Myocardial triglyceride content also increases during acute fasting, again suggesting that this energy store is not regulated simply by feeding-dependent humoral factors, such as insulin.35


Figure 1
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  		Figure 1 Diurnal variations in myocardial metabolism for the rat. Figure illustrates time during the sleep/wake cycle at which parameters of myocardial metabolism peak. Time is represented as Zeitgeber time (ZT). ZT0 is the dark-to-light phase transition. Shaded area represents the dark phase, a time at which rodents are awake. Note that diurnal variations in myocardial metabolism for the mouse appear to differ, compared with the rat (see text).

 
We have recently characterized diurnal variations in myocardial metabolism in ex vivo perfused working rat hearts.36,37 Allowing the heart to achieve a steady state in function and metabolism ex vivo enables exposure of the intrinsic properties of the myocardium. Although interdependent, carbohydrate and lipid metabolism will initially be discussed separately, for the purposes of clarity. In the case of myocardial carbohydrate metabolism, marked diurnal variations in exogenous glucose oxidation (i.e. glucose derived from the medium as opposed to intracellular glycogen) are observed, with increased rates (approximately two-fold) for hearts isolated during the awake phase.36,37 Increased rates of exogenous glucose oxidation could be mediated by increased glucose uptake, increased channelling of glucose into the glycolytic pathway (as opposed to glycogenesis), and/or increased coupling between glycolysis and pyruvate oxidation. Consistent with all three possibilities, we have observed increased myocardial GLUT4 protein levels, increased net glycogenolysis (as opposed to glycogenesis), and decreased lactate release, for rat hearts perfused during the awake phase.36,37

Taken together, the data currently available regarding intrinsic diurnal variations in rat heart glucose metabolism suggest an improved channelling of glucosyl units (derived from either extracellular glucose or glycogen) towards complete oxidation during the awake phase. These observations are consistent with anticipation of increased energy demand during the awake phase. However, these observations in myocardial glucose metabolism are not without contradiction for the in vivo scenarios in which the animal is either successful or unsuccessful in its forage for food. Increased capacity for glucose uptake and oxidation during the awake phase would be consistent with the fed state, while increased glycogenolysis capacity at this time would more likely be associated with the fasted state. Indeed myocardial glycogen content increases progressively during the awake phase in the ad libitum fed rat, suggesting that the predisposition (i.e. intrinsic property in the absence of extrinsic influence) towards glycogenolysis during the awake phase can be over-riden by neurohumoral influence in vivo (e.g. insulin). Thus, in terms of glucose metabolism, data available to date for the rat are more consistent with the hypothesis that the heart anticipates diurnal variations in workload, as opposed to feeding/fasting cycles.

Diurnal variations in oxidative vs. non-oxidative fatty acid metabolism have also been investigated in the rat heart. Unlike rates of exogenous glucose oxidation, exogenous oleate (the primary monounsaturated fatty acid within the circulation) oxidation rates do not exhibit a significant diurnal variation in ex vivo perfused rat hearts.36,37 However, channelling of oleate into non-oxidative pathways does exhibit a circadian rhythm, with increased synthesis of phospholipids, diacylglycerol, and triacylglycerol for hearts isolated during the sleep phase (the time at which circulating non-esterified fatty acids are elevated in the ad libitum fed rat).36,38 These observations for ex vivo perfused rat hearts are consistent with a peak in myocardial triglyceride content at the end of the sleep phase. Interestingly, the perfused rat heart exhibits increased susceptibility to fatty acid-mediated depression of cardiac power (derived from cardiac output) and efficiency during the sleep phase, suggesting that non-oxidative metabolism of fatty acids may mediate this phenomenon.36 A decreased susceptibility to fatty acid-mediated depression of myocardial contractile function during the awake phase is consistent with anticipation of increase workload and energetic demand at this time. This becomes increasingly important if the animal in the wild is unsuccessful in its forage for food, as the latter elevates circulating non-esterified fatty acids during the awake phase.39

The heart, as with additional organs responds to prolonged alterations in the environment through transcriptional events. In certain instances, these events can be relatively rapid, occurring within minutes to hours. The myocardium responds in this manner to a plethora of neurohumoral factors influenced by feeding/fasting cycles. These include circulating fatty acids, which induce a coordinated set of genes promoting fatty acid oxidation and concomitantly repressing glucose oxidation.40 We have previously reported that diurnal variations in the transcriptional responsiveness of the rat heart to fatty acids peak during the awake phase, consistent with anticipation of prolongation of the sleep-phase fast, enabling a rapid induction of genes promoting fatty acid metabolism when circulating levels of this substrate increase.38 Currently available data regarding diurnal variations in the oxidative and non-oxidative metabolism of carbohydrate and lipid by the rat heart, as well as transcriptional responsiveness, are consistent with anticipation of increased energy demand during the awake phase, while somewhat mixed results are observed regarding anticipation of feeding/fasting cycles. The latter may reflect an evolutionary advantage for the heart to ‘hedge its bets’, thereby preparing for both successful and unsuccessful foraging for food during the awake phase. In doing so, the heart will be able to adapt rapidly and appropriately to alterations in feeding-dependent neurohumoral factors (e.g. fatty acids, insulin), depending upon which situation unfolds.


   3. Potential mechanisms mediating diurnal variations in myocardial metabolism
Top
 Abstract
 1. Introduction
 2. Diurnal variations in...
 3. Potential mechanisms...
4. Potential mechanistic links...
 5. Interrelationship between...
 6. Summary
 Funding
 References
 
Modulation of myocardial metabolic flux occurs in response to numerous environmental stimuli. Many of these stimuli themselves exhibit diurnal variations, such that a large number of candidates potentially mediating diurnal variations in myocardial metabolism could be listed. Although many of the studies investigating diurnal variations in the intrinsic properties of myocardial metabolism have been performed utilizing ex vivo perfused hearts, thereby removing acute neurohumoral influences, the effects of neurohumoral factors on gene and protein expression prior to heart isolation cannot be discounted. In addition to extra cardiac stimuli, the circadian clock within the cardiomyocyte presents itself as an attractive potential modulator of myocardial metabolism. In an attempt to investigate the role of this cell autonomous mechanism, we have recently generated a mouse model in which the circadian clock is specifically disrupted only within the cardiomyocytes [termed cardiomyocyte clock mutant (CCM) mouse].39 Initial studies utilizing CCM mice have revealed a number of important observations. First, significant differences are observed between ex vivo perfused rat and wild-type mouse (FVB/N background) hearts. Unlike the rat heart, wild-type mouse hearts do not exhibit a diurnal variation in exogenous glucose oxidation rates.36,41 Furthermore, rates of myocardial lactate release tend to be elevated during the awake phase (whereas the opposite is observed for rat hearts). These differences are associated with distinct diurnal oscillations in the expression of several metabolic genes (e.g. ucp3, pdk4), which are phase-delayed (6 h) in the mouse, compared with the rat, heart.38,39 When glucose metabolism (glucose oxidation and lactate release) were compared between wild-type and CCM hearts perfused under basal conditions, no significant differences were observed.41 However, when challenged with an acute increase in workload, CCM hearts exhibited a marked attenuation in glycogenolysis (as assessed by endogenously derived lactate release), providing initial evidence that the circadian clock within the cardiomyocyte potentially regulates myocardial glycogen metabolism.41

Consistent with rat hearts, wild-type mouse hearts do not exhibit a significant diurnal variation in rates of exogenous oleate oxidation.36,37,41 However, independent of time of day, CCM hearts exhibit increased rates of exogenous oleate oxidation, and concomitant elevations in myocardial oxygen consumption.41 Similar to rat hearts perfused in the presence of elevated fatty acid levels, wild-type mouse hearts exhibit a diurnal variation in cardiac efficiency, peaking during the active phase.36,41 This diurnal variation is absent in CCM hearts, suggesting mediation by the circadian clock within the cardiomyocyte. To date, ex vivo characterization of diurnal variations in the non-oxidative metabolism of fatty acids has not been performed in either wild-type or CCM mouse hearts. However, we have recently reported an increased reliance of CCM hearts on endogenous substrates only when perfused in the presence of elevated oleate levels, suggestive of perturbations in triglyceride metabolism.42 Consistent with the latter, acute (16 h) fasting-induced triglyceride synthesis is abolished in CCM hearts.39 These data therefore suggest that the circadian clock within the cardiomyocyte likely regulates triglyceride metabolism.

Our initial studies investigating perturbations in myocardial metabolism following disruption of the cardiomyocyte circadian clock (i.e. CCM hearts) strongly support the hypothesis that this molecular mechanism influences turnover of endogenous substrates (i.e. glycogen and triglyceride). Direct regulation of the turnover of endogenous fuels by an endogenous mechanism is advantageous for the cell to anticipate diurnal variations in an environmental stimulus that is recurrent. Such is the case for diurnal variations in workload. In contrast, uptake and metabolism of exogenous substrates would more likely be under the influence of extracellular stimuli (i.e. neurohumoral factors). Nevertheless, a strong probability remains that the circadian clock enables the heart to anticipate diurnal variations in various neurohumoral influences, through modulation of myocardial responsiveness in a temporal fashion. Consistent with this concept, we have recently found that the circadian clock within the cardiomyocyte mediates diurnal variations in the responsiveness of the heart to increased workloads, at both contractile function and metabolic flux levels.41 The same is likely true for feeding-dependent humoral factors, such as fatty acids and insulin. Through the use of both in vitro (isolated cardiomyocytes) and in vivo (light/dark cycle manipulations and CCM mice) studies, we have recently reported that diurnal variations in the transcriptional responsiveness of the heart to fatty acids are mediated by the circadian clock within the cardiomyocyte, consistent with anticipation of prolongation of the sleep-phase fast (enabling rapid inductions of fatty acid oxidation promoting genes during the active phase only if circulating levels of this nutrient increase).39 Although diurnal variations in insulin sensitivity have not been reported for the heart, they have been observed at both the whole body and specific peripheral tissue levels (e.g. skeletal muscle).43–47 We have therefore initiated studies investigating whether the cardiomyocyte circadian clock influences myocardial insulin sensitivity, revealing a decreased sensitivity of CCM hearts to insulin (at the level of insulin-mediated Akt phosphorylation; unpublished results).

Together, our studies utilizing CCM hearts suggest that the intramyocellular circadian clock likely influences myocardial metabolism both directly (e.g. triglyceride and glycogen metabolism) and indirectly (through modulation of the sensitivity of the myocardium to workload, fatty acids, and insulin). In doing so, the circadian clock would allow the myocardium to prepare for multiple combinations of time-dependent stimuli. For example, increasing the sensitivity of the heart to insulin during the active phase (as observed for skeletal muscle and the whole body level) would enable rapid increases in exogenous glucose uptake if the animal was successful in its forage for food, but would not commit the myocardium to utilization of circulating glucose if the animal was unsuccessful in ending the sleep-phase fast.


   4. Potential mechanistic links between the circadian clock and myocardial metabolism
Top
 Abstract
 1. Introduction
 2. Diurnal variations in...
 3. Potential mechanisms...
 4. Potential mechanistic links...
5. Interrelationship between...
 6. Summary
 Funding
 References
 
The previous section of this article outlines data suggesting that the circadian clock within the cardiomyocyte both directly (in the case of triglyceride and glycogen turnover) and indirectly (through modulation of the responsiveness of the heart to workload, fatty acids, and insulin) regulates myocardial metabolism. An important next question relates to the identity of the mediators linking the cardiomyocyte circadian clock to myocardial metabolism. The circadian clock is transcriptionally-based, and as such output from this mechanism manifests initially at the level of altered gene expression.1,4 Accordingly, numerous studies have been performed investigating the identity of circadian clock-regulated genes. Both hypothesis testing (i.e. candidate gene) and hypothesis generating (i.e. microarray) approaches have been employed. Gene expression microarray studies reveal an extensive (~10% of myocardially expressed genes) and diverse set of genes whose expression oscillates in a circadian-like manner in wild-type mouse hearts.48,49 Many of these genes are known to influence processes such as transcription, translation, signal transduction, and metabolism. Oscillations in myocardial gene expression could be mediated by either extracellular (i.e. neurohumoral) or intracellular (i.e. circadian clock) influences. To investigate the contribution of the latter, we have recently performed a gene expression microarray study in wild-type vs. CCM hearts.41 We defined a gene as potentially being regulated by the circadian clock within the cardiomyocyte if it was found to exhibit a significant circadian oscillation in wild-type hearts, which is significantly attenuated in CCM hearts. This approach identified 548 and 176 genes as being potentially regulated by the circadian clock within atrial and ventricular cardiomyocytes, respectively.41 Among those genes identified, several of the encoded proteins are known to influence triglyceride metabolism, consistent with our observations that the circadian clock within the cardiomyocyte regulates triglyceride turnover (Table 1). These genes include agpat3 (1-acylglycerol-3-phosphate O-acyltransferase; enzyme involved in lipogenesis), dgat2 (diacylglycerol O-acyltransferase 2; enzyme involved in lipogenesis), s3–12 (lipid binding protein), and adpn (adiponutrin; enzyme involved in lipolysis).50–53 Consistent with impaired fasting-induced myocardial triglyceride synthesis, dgat2 and s3–14 are chronically repressed, while adpn is chronically induced, in CCM hearts.39,41 These data suggest that the circadian clock within the cardiomyocyte likely influences myocardial triglyceride metabolism through the coordinated regulation of genes involved in lipogenesis, lipid droplet stability, and lipolysis.


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  		Table 1 Correlations between altered myocardial gene expression and metabolic parameters in wild-type vs. cardiomyocyte clock mutant mice (CCM) (data obtained from references30,32)

 
Gene expression microarray analysis of CCM hearts may provide additional insight regarding the mechanisms by which the cardiomyocyte circadian clock influences myocardial metabolism, as summarized in Table 1. For example, relative to wild-type hearts, CCM hearts exhibit a chronic induction of genes inhibiting glycogenolysis [e.g. prkar1a (the inhibitory subunit of protein kinase A), ppp1cc (a catalytic subunit of protein phosphatase 1)] and a chronic repression of genes promoting glycolysis [e.g. pfkm (muscle phosphofructokinase)], consistent with decreased glycogen-derived lactate release.41 Similarly, elevated rates of oleate oxidation by perfused CCM hearts are associated with a chronic induction of fatp1 (fatty acid transport protein 1). Decreased gene expression of pik3r1 (p85{alpha} subunit of phosphoinositide-3-kinase) in CCM hearts is consistent with decreased myocardial insulin sensitivity.41 These observations provide novel avenues of pursuit for future research. Additional studies designed to investigate whether these alterations in gene expression are mirrored by concomitant changes in protein expression and activity will provide essential information regarding the mechanisms by which the circadian clock influences myocardial metabolism.

The transcriptional response of the heart to fatty acids also exhibits a diurnal variation, in a cardiomyocyte circadian clock-dependent manner.38,39 The primary mechanism by which the heart responds to fatty acids is through activation of the nuclear receptor sub-family, the peroxisome proliferator-activated receptors (PPARs).40 Both PPAR{alpha} and PPARβ/{delta} are highly expressed within the myocardium, and both induce genes promoting fatty acid oxidation.40 Consistent with the hypothesis that PPAR{alpha} potentially mediates diurnal variations in the responsiveness of the heart to fatty acids, we have shown that induction of fatty acid-responsive genes by the rat heart exhibits similar diurnal variations in response to fatty acids and specific PPAR{alpha} agonism (WY-14 643).38 More recently, Oishi et al.54 have suggested that PPAR{alpha} is a circadian clock-regulated gene in the liver. However, ppar{alpha} mRNA exhibits only a modest circadian oscillation in the normal myocardium, which neither persists in cultured cardiomyocytes nor is disrupted in CCM hearts, suggesting that the PPAR{alpha} gene may not be regulated by the cardiomyocyte circadian clock.6,38,41 Transcriptional activity of PPAR{alpha} is influenced not only at the level of gene expression, but is also affected post-translationally, through modulation in the availability of heterodimerization partners, co-activators, co-repressors, and ligands, as well as phosphorylation events.40,55 Studies investigating gene expression in wild-type vs. CCM hearts reveal potential regulation of proteins known to influence PPAR{alpha} transcriptional activity (e.g. pparbp, rev-erba{alpha}) by the circadian clock within the cardiomyocyte.41


   5. Interrelationship between nutrient intake and the intramyocellular circadian clock
Top
 Abstract
 1. Introduction
 2. Diurnal variations in...
 3. Potential mechanisms...
 4. Potential mechanistic links...
 5. Interrelationship between...
6. Summary
 Funding
 References
 
By definition, circadian clocks comprise a series of positive and negative feedback loops. It is therefore not surprising that, as with multiple biological processes, distinct circadian clock outputs appear to influence the timing of this mechanism. For example, Kaasik and Lee56 report evidence that the circadian clock regulates heme biosynthesis in the liver, and that heme levels in turn influence the timing of the circadian clock through interaction with specific clock components (e.g. PER proteins). Similarly, Rutter et al.57 report that lactate dehydrogenase is a direct circadian clock output gene in a neuroblastoma cell line, and that the transcriptional activity of the CLOCK homologue NPAS2 is sensitive to intracellular NAD+/NADH ratios. These data suggest that circadian clock-mediated oscillations in heme and NAD+/NADH metabolism may in turn feedback to influence the timing of the circadian clock, at least in a cell type specific manner. To date, circadian oscillations in myocardial heme or NAD+/NADH have not been reported. In the latter case, perturbations in the NAD+/NADH ratio are relatively small in the heart during extremes in workload, and myocardial lactate dehydrogenase activity exceeds glycolytic flux, questioning whether the feedback loop described by Rutter et al. would be operational in the myocardium.58,59 However, recent studies within our laboratory expose pbef1 (nicotinamide phosphoribosyltransferase; the flux generating enzyme in NAD biosynthesis) as being regulated by the circadian clock within the cardiomyocyte, consistent with previous observations that total NAD levels exhibit a circadian oscillation within the myocardium.41,60 Whether this would in turn influence myocardial metabolism and/or the cardiomyocyte circadian clock remains to be investigated.

The evidence described in previous sections of this review suggest that the intramyocellular circadian clock influences both carbohydrate and lipid metabolism. This raises the question as to whether alterations in carbohydrate and/or lipid metabolism, in turn, influence the timing of the intramyocellular circadian clock. Evidence in support of this possibility includes the observation that feeding is the strongest entrainment factor for peripheral circadian clocks, such as those within the heart.61 We have previously reported that uncontrolled insulin-dependent diabetes mellitus, which is associated with marked perturbations in circulating nutrients (hyperglycaemia and hyperlipidemia) and myocardial metabolism (increased fatty acid oxidation and concomitant depression of glucose oxidation), causes a phase shift in the myocardial circadian clock.62 Consistent with the possibility that altered circulating nutrients affect the timing of the circadian clock during diabetes, Hirota et al.63 have shown that glucose influences the expression of circadian clock genes in cultured Rat-1 fibroblasts. These observations encouraged us to investigate whether an elevation in glucose availability influenced the timing of the circadian clock within isolated cardiomyocytes. Unlike the observations in immortalized fibroblasts, we found that elevated glucose levels were without effect on the expression of circadian clock genes in isolated cardiomyocytes, raising the possibility that glucose may influence circadian clocks in a cell-type specific manner.6

Whether fatty acids influence the timing of peripheral circadian clocks is a question that has received significant attention recently. Yanagihara et al.64 reported that 8 weeks of high fat feeding in mice has essentially no effects on circadian clocks within visceral adipose tissue or liver. Satoh et al.29 also report a lack of effect of ad libitum high fat feeding on murine liver circadian clock. Consistent with these observations, we find that 4 weeks high fat feeding has no significant effect on any circadian clock gene oscillations in the rat heart (Figure 2), nor in skeletal muscle, liver or adipose tissue (unpublished results). This lack of effect is despite a 12 h phase shift in diurnal oscillations in circulating fatty acids between low and high fat fed rats, and a marked induction of fatty acid responsive genes in hearts isolated from high fat fed rats.38 Furthermore, we have previously reported that direct challenge of isolated adult rat cardiomyocytes with oleate has no effect on the timing of circadian clock gene oscillations.39 It should be noted that more recently Kohsaka et al.65 reported that high fat feeding in mice affects both central and peripheral clocks (although the heart was not investigated). The latter observations await confirmation. Taken together, no direct evidence currently exists in support of the hypothesis that nutrients (either glucose or fatty acids) influence the timing of the circadian clock within the cardiomyocyte.


Figure 2
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  		Figure 2 High fat feeding has no significant effect on circadian clocks within the rat heart. Rats were fed either low or high fat diets (10% and 60% calories from fat, respectively; Research Diets Inc.) for a total duration of 4 weeks. Hearts were isolated at 3 h intervals over a 24 h period, as described previously.38 Gene expression was measured through quantitative RT–PCR, as described previously.79,80 Genes investigated include brain and muscle ARNT-like 1 (bmal1; A), circadian locomotor output cycles kaput (clock; B), period 1 (per1; C), rev-erba{alpha} (D), albumin D-element binding protein (dbp; E), and E4 promoter binding protein 4 (e4bp4; F). Time is represented as Zeitgeber time (ZT). ZT0 is the dark-to-light phase transition.

 
Although macronutrient composition appears to have no direct effect on the circadian clock within the cardiomyocyte, this molecular mechanism does influence their metabolic fate. Nutrients are more than just a fuel for the myocardium, and are also capable of modulating membrane fluidity, intracellular signalling, ion homeostasis, and cell survival.66–68 As such, inability of the cardiomyocyte to adequately handle nutrients when in excess results in cellular dysfunction.69,70 This appears to be the case during diabetes mellitus, in which accumulation of intramyocellular glucose and fatty acid derivatives are associated with myocardial contractile dysfunction.69 Nutrient induced impairment of myocardial contractile dysfunction also appears to occur in a time-of-day dependent manner. An acute challenge of the rat heart with elevated fatty acid levels results in depression of cardiac power and efficiency only during the sleep phase, associated with an increased channelling of fatty acids into non-oxidative pathways.36 These observations raise the possibility that altered diurnal variations in circulating nutrients, such as fatty acids, may contribute towards disease progression by simply being elevated at an inappropriate time of the day. Consistent with such a hypothesis, myocardial contractile dysfunction during diabetes mellitus is associated with abnormal diurnal variations in circulating glucose and fatty acids, in both animal models and humans.62,71–73 This concept raises the possibility that normalization of diurnal variations in circulating nutrients may improve cardiac function during disease states, such as diabetes and obesity cardiomyopathy. One relatively straightforward way to achieve this goal would be through time-of-day restricted (meal) feeding.

Numerous studies investigating the influence of meal feeding on circulating markers of insulin sensitivity (e.g. fasting glucose and insulin levels) and cardiovascular disease risk (e.g. HDL and LDL levels) have been performed to date in both animal models and humans. Currently available information regarding human meal feeding studies is inconclusive. This is likely due to the limited number of controlled studies performed, with highly heterogeneous subject samples in terms of race/ethnicity, gender, and body weight.74 Most studies have included small numbers of subjects and short durations (e.g. 2 weeks) on specific feeding regimes. Meal feeding during Ramadan (1 meal in the evening only, for 1 month) is associated with beneficial alterations in several CVD risk factors, such as increased HDL and decreased LDL.75 In marked contrast, eating 3 meals per day for 2 weeks vs. 17 smaller snacks, was associated with the opposite effect (i.e. decreased HDL and increased LDL).76 Clearly, studies involving greater durations in altered feeding regimes and formal assessment of cardiovascular function are required. In the case of animal studies, protocols designed to lengthen inter-meal intervals invariably improve CVD risk markers and longevity.77,78 However, such feeding regimes typically result in reduced caloric intake, relative to ad libitum fed rodents, preventing dissociation between the potential influences of quantity of calories vs. time of day at which calories were ingested.

None of the studies described above have directly assessed the influence of long-term isocaloric meal feeding on myocardial contractile function. Nor have studies been reported in which the effects of temporarily controlled macronutrient availability on cardiovascular function have been investigated. Given the marked diurnal variations in the responsiveness of the myocardium to fatty acids (at transcriptional, metabolic flux, and contractile function levels), consumption of high fat diets at the initiation of the awake phase vs. at the end of the awake phase, may prove to be beneficial for cardiovascular function. Meal feeding elicits the additional benefit of fine-tuning the circadian clock, thereby synchronizing the myocardium with its environment. Conversely, consumption of excess nutrients at an inappropriate time of the day and/or loss of normal neurohumoral circadian rhythms (e.g. during diabetes mellitus) would be expected to result in dyssynchronization of the heart with its metabolic milieu, potentially promoting cardiovascular disease development (Figure 3).


Figure 3
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  		Figure 3 Hypothetical model illustrating the importance of synchronization between the heart and the neurohumoral milieu, in terms of myocardial contractile function.

 

   6. Summary
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 Abstract
 1. Introduction
 2. Diurnal variations in...
 3. Potential mechanisms...
 4. Potential mechanistic links...
 5. Interrelationship between...
 6. Summary
Funding
 References
 
The present review summarizes our current knowledge regarding circadian rhythms in myocardial metabolism. The rodent heart exhibits distinct diurnal variations in the oxidative and non-oxidative metabolism of carbohydrate and lipids. Through the use of CCM mice, we find that the circadian clock within the cardiomyocyte directly (in the case of triglyceride and glycogen turnover) and indirectly (through modulation of the responsiveness of the heart to workload, fatty acids, and insulin) influences myocardial metabolism in a time-of-day dependent manner. These observations are consistent with an ability of the heart to anticipate diurnal variations in workload and feeding/fasting cycles. In contrast to the timing of feeding, dietary macronutrient content does not appear to influence the circadian clock within the cardiomyocyte. Indirect evidence exists in support of the hypothesis that nutrient-controlled meal feeding may improve myocardial contractile function by synchronizing the heart with its metabolic milieu. Conversely, dyssynchronization of the myocardium with its environment, through disruption of the intramyocellular circadian clock and/or neurohumoral diurnal variations (that occur during diabetes mellitus, obesity, hypertension, ischaemic heart disease), will likely accelerate cardiovascular disease development.

Conflict of interest: neither M.S.B. nor M.E.Y. has conflicts of interest to disclose.


   Funding
Top
 Abstract
 1. Introduction
 2. Diurnal variations in...
 3. Potential mechanisms...
 4. Potential mechanistic links...
 5. Interrelationship between...
 6. Summary
 Funding
References
 
This work was supported by the National Heart, Lung, and Blood Institute (HL-074259; M.E.Y.), the USDA/ARS (6250-51000-044 and 6250-51000-046; M.E.Y. and M.S.B.), and Kraft Inc. (M.E.Y. and M.S.B.).


   References
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 Abstract
 1. Introduction
 2. Diurnal variations in...
 3. Potential mechanisms...
 4. Potential mechanistic links...
 5. Interrelationship between...
 6. Summary
 Funding
 References
 

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G. D. Lopaschuk and D. P. Kelly
Signalling in cardiac metabolism
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