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Karyn A. Esser - One of the best experts on this subject based on the ideXlab platform.
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the endogenous Molecular Clock orchestrates the temporal separation of substrate metabolism in skeletal muscle
Skeletal Muscle, 2015Co-Authors: Brian A Hodge, Brianna D. Harfmann, Elizabeth A. Schroder, Xiping Zhang, Lance A Riley, Jonathan H England, Karyn A. EsserAbstract:Background: Skeletal muscle is a major contributor to whole-body metabolism as it serves as a depot for both glucose and amino acids, and is a highly metabolically active tissue. Within skeletal muscle exists an intrinsic Molecular Clock mechanism that regulates the timing of physiological processes. A key function of the Clock is to regulate the timing of metabolic processes to anticipate time of day changes in environmental conditions. The purpose of this study was to identify metabolic genes that are expressed in a circadian manner and determine if these genes are regulated downstream of the intrinsic Molecular Clock by assaying gene expression in an inducible skeletal muscle-specific Bmal1 knockout mouse model (iMS-Bmal1 �/� ). Methods: We used circadian statistics to analyze a publicly available, high-resolution time-course skeletal muscle expression dataset. Gene ontology analysis was utilized to identify enriched biological processes in the skeletal muscle circadian transcriptome. We generated a tamoxifen-inducible skeletal muscle-specific Bmal1 knockout mouse model and performed a time-course microarray experiment to identify gene expression changes downstream of the Molecular Clock. Wheel activity monitoring was used to assess circadian behavioral rhythms in iMS-Bmal1 �/� and control iMS-Bmal1 +/+ mice. Results: The skeletal muscle circadian transcriptome was highly enriched for metabolic processes. Acrophase analysis of circadian metabolic genes revealed a temporal separation of genes involved in substrate utilization and storage over a 24-h period. A number of circadian metabolic genes were differentially expressed in the skeletal muscle of the iMS-Bmal1 �/� mice. The iMS-Bmal1 �/� mice displayed circadian behavioral rhythms indistinguishable from iMS-Bmal1 +/+ mice. We also observed a gene signature indicative of a fast to slow fiber-type shift and a more oxidative skeletal muscle in the iMS-Bmal1 �/� model. Conclusions: These data provide evidence that the intrinsic Molecular Clock in skeletal muscle temporally regulates genes involved in the utilization and storage of substrates independent of circadian activity. Disruption of this mechanism caused by phase shifts (that is, social jetlag) or night eating may ultimately diminish skeletal muscle’ sa bility to efficiently maintain metabolic homeostasis over a 24-h period.
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Circadian rhythms, the Molecular Clock, and skeletal muscle.
Journal of Biological Rhythms, 2014Co-Authors: Brianna D. Harfmann, Elizabeth A. Schroder, Karyn A. EsserAbstract:Circadian rhythms are the approximate 24-h biological cycles that function to prepare an organism for daily environmental changes. They are driven by the Molecular Clock, a transcriptional:translational feedback mechanism that in mammals involves the core Clock genes Bmal1, Clock, Per1/2, and Cry1/2. The Molecular Clock is present in virtually all cells of an organism. The central Clock in the suprachiasmatic nucleus (SCN) has been well studied, but the Clocks in the peripheral tissues, such as heart and skeletal muscle, have just begun to be investigated. Skeletal muscle is one of the largest organs in the body, comprising approximately 45% of total body mass. More than 2300 genes in skeletal muscle are expressed in a circadian pattern, and these genes participate in a wide range of functions, including myogenesis, transcription, and metabolism. The circadian rhythms of skeletal muscle can be entrained both indirectly through light input to the SCN and directly through time of feeding and activity. It is critical for the skeletal muscle Molecular Clock not only to be entrained to the environment but also to be in synchrony with rhythms of other tissues. When circadian rhythms are disrupted, the observed effects on skeletal muscle include fiber-type shifts, altered sarcomeric structure, reduced mitochondrial respiration, and impaired muscle function. Furthermore, there are detrimental effects on metabolic health, including impaired glucose tolerance and insulin sensitivity, which skeletal muscle likely contributes to considering it is a key metabolic tissue. These data indicate a critical role for skeletal muscle circadian rhythms for both muscle and systems health. Future research is needed to determine the mechanisms of Molecular Clock function in skeletal muscle, identify the means by which skeletal muscle entrainment occurs, and provide a stringent comparison of circadian gene expression across the diverse tissue system of skeletal muscle.
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The cardiomyocyte Molecular Clock, regulation of Scn5a, and arrhythmia susceptibility
American journal of physiology. Cell physiology, 2013Co-Authors: Elizabeth A. Schroder, Karyn A. Esser, Mellani Lefta, Xiping Zhang, Daniel C. Bartos, Han-zhong Feng, Yihua Zhao, Abhijit Patwardhan, Jian Ping Jin, Brian P. DelisleAbstract:The Molecular Clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core Molecular Clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the Molecular Clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1(-/-)) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCSΔBmal1(-/-) hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na(+) channel (Na(V)1.5), was circadianly expressed in control mouse and rat hearts but not in iCSΔBmal1(-/-) hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of Clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCSΔBmal1(-/-) hearts was associated with decreased levels of Na(V)1.5 and Na(+) current in ventricular myocytes. We conclude that disruption of the Molecular Clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte Molecular Clock and factors that influence arrhythmia susceptibility in humans.
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Circadian rhythms, the Molecular Clock, and skeletal muscle.
Current topics in developmental biology, 2011Co-Authors: Mellani Lefta, Gretchen Wolff, Karyn A. EsserAbstract:Almost all organisms ranging from single cell bacteria to humans exhibit a variety of behavioral, physiological, and biochemical rhythms. In mammals, circadian rhythms control the timing of many physiological processes over a 24-h period, including sleep-wake cycles, body temperature, feeding, and hormone production. This body of research has led to defined characteristics of circadian rhythms based on period length, phase, and amplitude. Underlying circadian behaviors is a Molecular Clock mechanism found in most, if not all, cell types including skeletal muscle. The mammalian Molecular Clock is a complex of multiple oscillating networks that are regulated through transcriptional mechanisms, timed protein turnover, and input from small molecules. At this time, very little is known about circadian aspects of skeletal muscle function/metabolism but some progress has been made on understanding the Molecular Clock in skeletal muscle. The goal of this chapter is to provide the basic terminology and concepts of circadian rhythms with a more detailed review of the current state of knowledge of the Molecular Clock, with reference to what is known in skeletal muscle. Research has demonstrated that the Molecular Clock is active in skeletal muscles and that the muscle-specific transcription factor, MyoD, is a direct target of the Molecular Clock. Skeletal muscle of Clock-compromised mice, Bmal1−/− and ClockΔ19 mice, are weak and exhibit significant disruptions in expression of many genes required for adult muscle structure and metabolism. We suggest that the interaction between the Molecular Clock, MyoD, and metabolic factors, such as PGC-1, provide a potential system of feedback loops that may be critical for both maintenance and adaptation of skeletal muscle.
Hervé Philippe - One of the best experts on this subject based on the ideXlab platform.
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The timing of eukaryotic evolution: does a relaxed Molecular Clock reconcile proteins and fossils?
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Emmanuel Douzery, Frédéric Delsuc, Elizabeth A Snell, Eric Bapteste, Hervé PhilippeAbstract:The use of nucleotide and amino acid sequences allows improved understanding of the timing of evolutionary events of life on earth. Molecular estimates of divergence times are, however, controversial and are generally much more ancient than suggested by the fossil record. The limited number of genes and species explored and pervasive variations in evolutionary rates are the most likely sources of such discrepancies. Here we compared concatenated amino acid sequences of 129 proteins from 36 eukaryotes to determine the divergence times of several major clades, including animals, fungi, plants, and various protists. Due to significant variations in their evolutionary rates, and to handle the uncertainty of the fossil record, we used a Bayesian relaxed Molecular Clock simultaneously calibrated by six paleontological constraints. We show that, according to 95% credibility intervals, the eukaryotic kingdoms diversified 950-1,259 million years ago (Mya), animals diverged from choanoflagellates 761-957 Mya, and the debated age of the split between protostomes and deuterostomes occurred 642-761 Mya. The divergence times appeared to be robust with respect to prior assumptions and paleontological calibrations. Interestingly, these relaxed Clock time estimates are much more recent than those obtained under the assumption of a global Molecular Clock, yet bilaterian diversification appears to be approximately 100 million years more ancient than the Cambrian boundary.
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the timing of eukaryotic evolution does a relaxed Molecular Clock reconcile proteins and fossils
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Emmanuel Douzery, Frédéric Delsuc, Elizabeth A Snell, Eric Bapteste, Hervé PhilippeAbstract:The use of nucleotide and amino acid sequences allows improved understanding of the timing of evolutionary events of life on earth. Molecular estimates of divergence times are, however, controversial and are generally much more ancient than suggested by the fossil record. The limited number of genes and species explored and pervasive variations in evolutionary rates are the most likely sources of such discrepancies. Here we compared concatenated amino acid sequences of 129 proteins from 36 eukaryotes to determine the divergence times of several major clades, including animals, fungi, plants, and various protists. Due to significant variations in their evolutionary rates, and to handle the uncertainty of the fossil record, we used a Bayesian relaxed Molecular Clock simultaneously calibrated by six paleontological constraints. We show that, according to 95% credibility intervals, the eukaryotic kingdoms diversified 950–1,259 million years ago (Mya), animals diverged from choanoflagellates 761–957 Mya, and the debated age of the split between protostomes and deuterostomes occurred 642–761 Mya. The divergence times appeared to be robust with respect to prior assumptions and paleontological calibrations. Interestingly, these relaxed Clock time estimates are much more recent than those obtained under the assumption of a global Molecular Clock, yet bilaterian diversification appears to be ≈100 million years more ancient than the Cambrian boundary.
Sebastián Duchêne - One of the best experts on this subject based on the ideXlab platform.
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The Molecular Clock of Mycobacterium tuberculosis.
PLoS pathogens, 2019Co-Authors: Fabrizio Menardo, Sebastián Duchêne, Daniela Brites, Sebastien GagneuxAbstract:The Molecular Clock and its phylogenetic applications to genomic data have changed how we study and understand one of the major human pathogens, Mycobacterium tuberculosis (MTB), the etiologic agent of tuberculosis. Genome sequences of MTB strains sampled at different times are increasingly used to infer when a particular outbreak begun, when a drug-resistant clone appeared and expanded, or when a strain was introduced into a specific region. Despite the growing importance of the Molecular Clock in tuberculosis research, there is a lack of consensus as to whether MTB displays a Clocklike behavior and about its rate of evolution. Here we performed a systematic study of the Molecular Clock of MTB on a large genomic data set (6,285 strains), covering different epidemiological settings and most of the known global diversity. We found that sampling times below 15-20 years were often insufficient to calibrate the Clock of MTB. For data sets where such calibration was possible, we obtained a Clock rate between 1x10-8 and 5x10-7 nucleotide changes per-site-per-year (0.04-2.2 SNPs per-genome-per-year), with substantial differences between clades. These estimates were not strongly dependent on the time of the calibration points as they changed only marginally when we used epidemiological isolates (sampled in the last 40 years) or three ancient DNA samples (about 1,000 years old) to calibrate the tree. Additionally, the uncertainty and the discrepancies in the results of different methods were sometimes large, highlighting the importance of using different methods, and of considering carefully their assumptions and limitations.
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The Molecular Clock of Mycobacterium tuberculosis
2019Co-Authors: Fabrizio Menardo, Sebastián Duchêne, Daniela Brites, Sebastien GagneuxAbstract:The Molecular Clock and its phylogenetic applications to genomic data have changed how we study and understand one of the major human pathogens, Mycobacterium tuberculosis (MTB), the causal agent of tuberculosis. Genome sequences of MTB strains sampled at different times are increasingly used to infer when a particular outbreak begun, when a drug resistant clone appeared and expanded, or when a strain was introduced into a specific region. Despite the growing importance of the Molecular Clock in tuberculosis research, there is a lack of consensus as to whether MTB displays a Clocklike behavior and about its rate of evolution. Here we performed a systematic study of the MTB Molecular Clock on a large genomic data set (6,285 strains), covering most of the global MTB diversity and representing different epidemiological settings. We found wide variation in the degree of Clocklike structure among data sets, indicating that sampling times are sometimes insufficient to calibrate the Clock of MTB. For data sets with temporal structure, we found that MTB genomes accumulate between 1x10-8 and 5x10-7 nucleotide changes per-site-per-year, which corresponds to 0.04 - 2.2 SNPs per-genome-per-year. Contrary to what expected, these estimates were not dependent on the time of the calibration points as they did not change significantly when we used epidemiological isolates (sampled in the last 40 years) or ancient DNA samples (about 1,000 years old) to calibrate the tree. Additionally, the uncertainty and the discrepancies in the results of different methods were often large, highlighting the importance of using different methods, and of considering carefully their assumptions and limitations.
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Molecular-Clock methods for estimating evolutionary rates and timescales.
Molecular ecology, 2014Co-Authors: Sebastián DuchêneAbstract:The Molecular Clock presents a means of estimating evolutionary rates and timescales using genetic data. These estimates can lead to important insights into evolutionary processes and mechanisms, as well as providing a framework for further biological analyses. To deal with rate variation among genes and among lineages, a diverse range of Molecular-Clock methods have been developed. These methods have been implemented in various software packages and differ in their statistical properties, ability to handle different models of rate variation, capacity to incorporate various forms of calibrating information and tractability for analysing large data sets. Choosing a suitable Molecular-Clock model can be a challenging exercise, but a number of model-selection techniques are available. In this review, we describe the different forms of evolutionary rate heterogeneity and explain how they can be accommodated in Molecular-Clock analyses. We provide an outline of the various Clock methods and models that are available, including the strict Clock, local Clocks, discrete Clocks and relaxed Clocks. Techniques for calibration and Clock-model selection are also described, along with methods for handling multilocus data sets. We conclude our review with some comments about the future of Molecular Clocks.
Masayuki Ikeda - One of the best experts on this subject based on the ideXlab platform.
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Histamine Regulates Molecular Clock Oscillations in Human Retinal Pigment Epithelial Cells via H1 Receptors.
Frontiers in Endocrinology, 2018Co-Authors: Eri Morioka, Yuzuki Kanda, Hayato Koizumi, Tsubasa Miyamoto, Masayuki IkedaAbstract:Vertebrate eyes are known to contain circadian Clocks, but their regulatory mechanisms remain largely unknown. To address this, we used a cell line from human retinal pigment epithelium (hRPE-YC) with stable coexpression of reporters for Molecular Clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). We observed concentration-dependent increases in cytosolic Ca2+ concentrations after treatment with histamine (1–100 µM) and complete suppression of histamine-induced Ca2+ mobilizations by H1 histamine receptor (H1R) antagonist d-chlorpheniramine in hRPE-YC cells. Consistently, real-time RT-PCR assays revealed that H1R showed the highest expression among the four subtypes (H1–H4) of histamine receptors in hRPE-YC cells. Stimulation of hRPE-YC cells with histamine transiently increased nuclear localization of phosphorylated CREB, a Ca2+/cAMP-responsible transcriptional factor that regulates Clock gene transcriptions. Administration of histamine also shifted the Bmal1-luciferase rhythms with a type-1 phase-response curve, similar to previous results with carbachol stimulations. Treatment of hRPE-YC cells with d-chlorpheniramine or with more specific H1R antagonist, ketotifen, blocked the histamine-induced phase-shifts. Furthermore, an H2 histamine receptor agonist, amthamine, had little effect on the Bmal1-luciferase rhythms. Although the function of the in vivo histaminergic system within the eye remains obscure, the present results suggest histaminergic control of the Molecular Clock via H1R in retinal pigment epithelial cells. Also, since d-chlorpheniramine and ketotifen have been widely used (e.g., to treat allergy and inflammation) in our daily life and thus raise a possible cause for circadian rhythm disorders by improper use of antihistamines.
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Histamine Regulates Molecular Clock Oscillations in Human Retinal Pigment Epithelial Cells via H1 Receptors
Frontiers Media S.A., 2018Co-Authors: Eri Morioka, Yuzuki Kanda, Hayato Koizumi, Tsubasa Miyamoto, Masayuki IkedaAbstract:Vertebrate eyes are known to contain circadian Clocks, but their regulatory mechanisms remain largely unknown. To address this, we used a cell line from human retinal pigment epithelium (hRPE-YC) with stable coexpression of reporters for Molecular Clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). We observed concentration-dependent increases in cytosolic Ca2+ concentrations after treatment with histamine (1–100 µM) and complete suppression of histamine-induced Ca2+ mobilizations by H1 histamine receptor (H1R) antagonist d-chlorpheniramine (d-CPA) in hRPE-YC cells. Consistently, real-time RT-PCR assays revealed that H1R showed the highest expression among the four subtypes (H1–H4) of histamine receptors in hRPE-YC cells. Stimulation of hRPE-YC cells with histamine transiently increased nuclear localization of phosphorylated Ca2+/cAMP-response element-binding protein that regulates Clock gene transcriptions. Administration of histamine also shifted the Bmal1-luciferase rhythms with a type-1 phase-response curve, similar to previous results with carbachol stimulations. Treatment of hRPE-YC cells with d-CPA or with more specific H1R antagonist, ketotifen, blocked the histamine-induced phase shifts. Furthermore, an H2 histamine receptor agonist, amthamine, had little effect on the Bmal1-luciferase rhythms. Although the function of the in vivo histaminergic system within the eye remains obscure, the present results suggest histaminergic control of the Molecular Clock via H1R in retinal pigment epithelial cells. Also, since d-CPA and ketotifen have been widely used (e.g., to treat allergy and inflammation) in our daily life and thus raise a possible cause for circadian rhythm disorders by improper use of antihistamines
Elizabeth A. Schroder - One of the best experts on this subject based on the ideXlab platform.
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the endogenous Molecular Clock orchestrates the temporal separation of substrate metabolism in skeletal muscle
Skeletal Muscle, 2015Co-Authors: Brian A Hodge, Brianna D. Harfmann, Elizabeth A. Schroder, Xiping Zhang, Lance A Riley, Jonathan H England, Karyn A. EsserAbstract:Background: Skeletal muscle is a major contributor to whole-body metabolism as it serves as a depot for both glucose and amino acids, and is a highly metabolically active tissue. Within skeletal muscle exists an intrinsic Molecular Clock mechanism that regulates the timing of physiological processes. A key function of the Clock is to regulate the timing of metabolic processes to anticipate time of day changes in environmental conditions. The purpose of this study was to identify metabolic genes that are expressed in a circadian manner and determine if these genes are regulated downstream of the intrinsic Molecular Clock by assaying gene expression in an inducible skeletal muscle-specific Bmal1 knockout mouse model (iMS-Bmal1 �/� ). Methods: We used circadian statistics to analyze a publicly available, high-resolution time-course skeletal muscle expression dataset. Gene ontology analysis was utilized to identify enriched biological processes in the skeletal muscle circadian transcriptome. We generated a tamoxifen-inducible skeletal muscle-specific Bmal1 knockout mouse model and performed a time-course microarray experiment to identify gene expression changes downstream of the Molecular Clock. Wheel activity monitoring was used to assess circadian behavioral rhythms in iMS-Bmal1 �/� and control iMS-Bmal1 +/+ mice. Results: The skeletal muscle circadian transcriptome was highly enriched for metabolic processes. Acrophase analysis of circadian metabolic genes revealed a temporal separation of genes involved in substrate utilization and storage over a 24-h period. A number of circadian metabolic genes were differentially expressed in the skeletal muscle of the iMS-Bmal1 �/� mice. The iMS-Bmal1 �/� mice displayed circadian behavioral rhythms indistinguishable from iMS-Bmal1 +/+ mice. We also observed a gene signature indicative of a fast to slow fiber-type shift and a more oxidative skeletal muscle in the iMS-Bmal1 �/� model. Conclusions: These data provide evidence that the intrinsic Molecular Clock in skeletal muscle temporally regulates genes involved in the utilization and storage of substrates independent of circadian activity. Disruption of this mechanism caused by phase shifts (that is, social jetlag) or night eating may ultimately diminish skeletal muscle’ sa bility to efficiently maintain metabolic homeostasis over a 24-h period.
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Circadian rhythms, the Molecular Clock, and skeletal muscle.
Journal of Biological Rhythms, 2014Co-Authors: Brianna D. Harfmann, Elizabeth A. Schroder, Karyn A. EsserAbstract:Circadian rhythms are the approximate 24-h biological cycles that function to prepare an organism for daily environmental changes. They are driven by the Molecular Clock, a transcriptional:translational feedback mechanism that in mammals involves the core Clock genes Bmal1, Clock, Per1/2, and Cry1/2. The Molecular Clock is present in virtually all cells of an organism. The central Clock in the suprachiasmatic nucleus (SCN) has been well studied, but the Clocks in the peripheral tissues, such as heart and skeletal muscle, have just begun to be investigated. Skeletal muscle is one of the largest organs in the body, comprising approximately 45% of total body mass. More than 2300 genes in skeletal muscle are expressed in a circadian pattern, and these genes participate in a wide range of functions, including myogenesis, transcription, and metabolism. The circadian rhythms of skeletal muscle can be entrained both indirectly through light input to the SCN and directly through time of feeding and activity. It is critical for the skeletal muscle Molecular Clock not only to be entrained to the environment but also to be in synchrony with rhythms of other tissues. When circadian rhythms are disrupted, the observed effects on skeletal muscle include fiber-type shifts, altered sarcomeric structure, reduced mitochondrial respiration, and impaired muscle function. Furthermore, there are detrimental effects on metabolic health, including impaired glucose tolerance and insulin sensitivity, which skeletal muscle likely contributes to considering it is a key metabolic tissue. These data indicate a critical role for skeletal muscle circadian rhythms for both muscle and systems health. Future research is needed to determine the mechanisms of Molecular Clock function in skeletal muscle, identify the means by which skeletal muscle entrainment occurs, and provide a stringent comparison of circadian gene expression across the diverse tissue system of skeletal muscle.
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The cardiomyocyte Molecular Clock, regulation of Scn5a, and arrhythmia susceptibility
American journal of physiology. Cell physiology, 2013Co-Authors: Elizabeth A. Schroder, Karyn A. Esser, Mellani Lefta, Xiping Zhang, Daniel C. Bartos, Han-zhong Feng, Yihua Zhao, Abhijit Patwardhan, Jian Ping Jin, Brian P. DelisleAbstract:The Molecular Clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core Molecular Clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the Molecular Clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCSΔBmal1(-/-)) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCSΔBmal1(-/-) hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na(+) channel (Na(V)1.5), was circadianly expressed in control mouse and rat hearts but not in iCSΔBmal1(-/-) hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of Clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCSΔBmal1(-/-) hearts was associated with decreased levels of Na(V)1.5 and Na(+) current in ventricular myocytes. We conclude that disruption of the Molecular Clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte Molecular Clock and factors that influence arrhythmia susceptibility in humans.
