Calcium Signaling in Cardiac Myocytes

Fearnley, C; Roderick, H. Llewelyn; Bootman, Martin D.

doi:10.1101/cshperspect.a004242

Cited by 226 publications

(235 citation statements)

References 144 publications

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“…1E). A more in-depth evaluation of the data using density plots revealed that pathways related to hypertrophic signaling, sarcomere organization (actin cytoskeleton), calcium, and cAMP-mediated signaling (27) and integrin signaling were significantly up-regulated (P ≤ 0.01) in both HAH and 1y-CM samples, suggesting in vitro maturation processes physiologically simulate the in vivo cardiac maturation ( Fig. 1 E-I and SI Appendix, Fig.…”

Section: In Vitro Cardiac Maturation Physiologically Simulates In Vivmentioning

confidence: 99%

“…Examination of the transcript levels of all significantly regulated genes [P ≤ 0.001 and fold change (FC) ≥ 2] in the abovementioned samples, using Ingenuity Pathway Analysis (IPA), revealed several interesting patterns and groups across the different samples. Cardiac maturation is known to improve Ca handling (27), fatty acid metabolism (9,28), and sarcomere organization (29) and results in the down-regulation of glucose metabolism/insulin signaling (30), cell proliferation (31), and pluripotency. Twelve categories reflecting these parameters are presented as a heat map ( Fig.…”

Section: In Vitro Cardiac Maturation Physiologically Simulates In Vivmentioning

confidence: 99%

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Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Kuppusamy

Jones²,

Sperber

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

229

218

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In metazoans, transition from fetal to adult heart is accompanied by a switch in energy metabolism-glycolysis to fatty acid oxidation. The molecular factors regulating this metabolic switch remain largely unexplored. We first demonstrate that the molecular signatures in 1-year (y) matured human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are similar to those seen in in vivo-derived mature cardiac tissues, thus making them an excellent model to study human cardiac maturation. We further show that let-7 is the most highly up-regulated microRNA (miRNA) family during in vitro human cardiac maturation. Gain-and loss-of-function analyses of let-7g in hESC-CMs demonstrate it is both required and sufficient for maturation, but not for early differentiation of CMs. Overexpression of let-7 family members in hESC-CMs enhances cell size, sarcomere length, force of contraction, and respiratory capacity. Interestingly, large-scale expression data, target analysis, and metabolic flux assays suggest this let-7-driven CM maturation could be a result of down-regulation of the phosphoinositide 3 kinase (PI3K)/AKT protein kinase/insulin pathway and an up-regulation of fatty acid metabolism. These results indicate let-7 is an important mediator in augmenting metabolic energetics in maturing CMs. Promoting maturation of hESC-CMs with let-7 overexpression will be highly significant for basic and applied research.everal coronary heart diseases (CHDs) are characterized by cardiac dysfunctions predominantly manifested during cardiac maturation (1, 2). Dramatic changes in energy metabolism occur during this postnatal cardiac maturation (3). At early embryonic development, glycolysis is a major source of energy for cardiomyocytes (CMs) (4, 5). However, as the cardiomyocytes mature, mitochondrial oxidative metabolism increases with fatty acid oxidation, providing 90% of the heart's energy demands (6-8). This switch in cardiac metabolism has been shown to have important implications during in vivo cardiac maturation (9). In contrast to the relatively advanced knowledge of the genetic network that contributes to heart development during embryogenesis (10, 11), molecular factors that regulate peri-and postnatal cardiac maturation, particularly in relation to the metabolic switch, remain largely unclear. So far, studies to understand the transition of the glycolysisdependent fetal heart to oxidative metabolism in the adult heart have been mostly related to the peroxisome proliferatoractivated receptor (PPAR)/estrogen-related receptor/PPARγ coactivator-1α circuit (7,8,12). However, it is currently unknown what other factors act upstream or in synergy with this pathway in controlling cardiac energetics.miRNAs have emerged as key factors in controlling the complex regulatory network in a developing heart (13). Genetic studies that enrich or deplete miRNAs in specific cardiac tissue types and large-scale gene expression studies have demonstrated that they achieve such complex control at the level of cardiac gene expression (14-16). We sou...

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Section: In Vitro Cardiac Maturation Physiologically Simulates In Vivmentioning

confidence: 99%

Section: In Vitro Cardiac Maturation Physiologically Simulates In Vivmentioning

confidence: 99%

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Kuppusamy

Jones²,

Sperber

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

229

218

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“…Calcium, an essential nutrient with an important role in bone health, is required for vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion (Anderson et al, 1993;Ambudkar, 2011;Fearnley et al, 2011;Rosenberg and Spitzer, 2011). The health benefi ts of calcium are related to bone health and osteoporosis, cardiovascular disease, blood pressure regulation and hypertension, kid- ney stones, and weight management (Burtis et al, 1993;Flynn, 2003;Tylavsky et al, 2008;Astrup, 2011;Meier and Kranzlin, 2011;).…”

Section: Nutritional Value Of Beefmentioning

confidence: 99%

Genetic parameters for concentrations of minerals in longissimus muscle and their associations with palatability traits in Angus cattle1

Mateescu

Garmyn

Tait

et al. 2013

Journal of Animal Science

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The objective of this study was to estimate genetic parameters for concentrations of minerals in LM and to evaluate their associations with beef palatability traits. Samples of LM from 2,285 Angus cattle were obtained and fabricated into steaks for analysis of mineral concentrations and for trained sensory panel assessments. Nine minerals, including calcium, copper, iron, magnesium, manganese, phosphorus, potassium, sodium, and zinc, were quantified. Restricted maximum likelihood procedures were used to obtain estimates of variance and covariance components under a multiple-trait animal model. Estimates of heritability for mineral concentrations in LM varied from 0.01 to 0.54. Iron and sodium were highly and moderately heritable, respectively, whereas the other minerals were lowly heritable except for calcium, copper, and manganese, which exhibited no genetic variation. Strong positive genetic correlations existed between iron and zinc (0. ABSTRACT: The objective of this study was to estimate genetic parameters for concentrations of minerals in LM and to evaluate their associations with beef palatability traits. Samples of LM from 2,285 Angus cattle were obtained and fabricated into steaks for analysis of mineral concentrations and for trained sensory panel assessments. Nine minerals, including calcium, copper, iron, magnesium, manganese, phosphorus, potassium, sodium, and zinc, were quantifi ed. Restricted maximum likelihood procedures were used to obtain estimates of variance and covariance components under a multiple-trait animal model. Estimates of heritability for mineral concentrations in LM varied from 0.01 to 0.54. Iron and sodium were highly and moderately heritable, respectively, whereas the other minerals were lowly heritable except for calcium, copper, and manganese, which exhibited no genetic variation. Strong positive genetic correlations existed between iron and zinc (0.49, P < 0.05), between magnesium and phosphorus (0.88, P < 0.05), between magnesium and sodium (0.68, P < 0.05), and between phosphorus and potassium (0.69, P < 0.05). Overall tenderness assessed by trained sensory panelists was positively associated with manganese, potassium, and sodium and negatively associated with phosphorus and zinc concentrations (P < 0.05). Juiciness assessed by trained sensory panelists was negatively associated with magnesium and positively associated with manganese and sodium concentrations (P < 0.05). Livery or metallic fl avor was not associated with any of the minerals (P > 0.05). Beefy fl avor was positively associated with calcium, iron, and zinc and negatively associated with sodium concentration, whereas a painty or fi shy fl avor was positively associated with sodium and negatively associated with calcium and potassium concentrations (P < 0.05). Beef is a major contributor of iron and zinc in the human diet, and these results demonstrate suffi cient genetic variation for these traits to be improved through marker-assisted selection programs without compromising beef palatability. 05). Li...

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“…However, scientific interest is not limited to the occurrence of Ca 2ϩ induced Ca 2ϩ release (CICR) per se but also focuses on where, how much, and how fast the Ca 2ϩ increases occur because the signaling information is encoded in all of these properties. 4 Although cardiac Ca 2ϩ transients appear homogeneous under physiological conditions, they arise from the coordinated activity of many microscopic ECC units, 3 comprising voltage operated Ca 2ϩ channels in the plasma membrane communicating to CICR channels, the ryanodine receptors (RyR), in the membrane of the Ca 2ϩ storing organelle, the sarcoplasmic reticulum (SR). 5 The reliable and repetitive fast communication between these two proteins ensures robust ECC and effective contractility of the myocyte eventually determining the mechanical performance of the entire heart.…”

mentioning

confidence: 99%

Noise-Free Visualization of Microscopic Calcium Signaling by Pixel-Wise Fitting

Tian

Kaestner

Lipp

2012

Circulation Research

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Rationale: Our insights into physiological and pathophysiological cardiac excitation-contraction coupling has greatly benefited from significant advancement in optical technologies such as high-speed confocal microscopy. This has pushed pixel dwell times into the time domain of nanoseconds, resulting in low signal-to-noise ratios, which have limited data analysis and interpretation.Objective: Line scan imaging has been and still is dominant in high speed confocal recording. It allows analysis only of a small fraction of a cell's cross section (1.5%), but the appreciation of spatiotemporal fine details of excitation-contraction coupling is instrumental for the further understanding of pathological mechanisms. We aim to provide a novel analysis tool to extract otherwise hidden fine details in cardiac excitation-contraction coupling from high-speed 2-dimensional confocal image series. Methods and Results:We demonstrate that high-speed 2-dimensional confocal data (150 frames/s) can be analyzed quantitatively by a pixel-wise fitting approach, using a mathematical formalism to phenomenologically describe local calcium transients. Such an approach produces virtually noise-free fluorescence data originating from minute volumes (0.025 femtoliter) and allows extraction of detailed and most importantly quantitative and mechanistically novel information on microscopic calcium signaling and excitation-contraction coupling in a robust manner. Conclusions:Pixel-wise fitting provides novel insights into cardiac excitation-contraction coupling. Specifically, it revealed microscopic calcium alternans on the level of individual coupling sites. Microscopic calcium alternans is an early precursor of cellular alternans and as such will shed more light onto this mechanism leading to cardiac arrhythmia. (Circ Res. 2012;111:17-27.) Key Words: excitation-contraction coupling Ⅲ calcium-induced calcium release Ⅲ noise-free image sequences Ⅲ alternans Ⅲ arrhythmogenic precursor Ⅲ Ca 2ϩ transients H igh-resolution live-cell imaging of subcellular signaling events has greatly fostered our understanding of cardiac physiology and pathophysiology. 1 In this, a major driving force was the advancement in laser-scanning technology that enabled ultrafast confocal imaging (Ͼ100 frames/s) without compromising the optical resolution. 2 Although researchers are technically able to follow fast subcellular signaling, such as excitation-contraction coupling (ECC) in cardiac myocytes, 3 decreasing the single pixel dwell times and concomitant decreases in the signal-to-noise ratio (SNR) have limited the progress. However, scientific interest is not limited to the occurrence of Ca 2ϩ induced Ca 2ϩ release (CICR) per se but also focuses on where, how much, and how fast the Ca 2ϩ increases occur because the signaling information is encoded in all of these properties. 4 Although cardiac Ca 2ϩ transients appear homogeneous under physiological conditions, they arise from the coordinated activity of many microscopic ECC units, 3 comprising voltage operated Ca 2ϩ ch...

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Calcium Signaling in Cardiac Myocytes

Cited by 226 publications

References 144 publications

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Genetic parameters for concentrations of minerals in longissimus muscle and their associations with palatability traits in Angus cattle1

Noise-Free Visualization of Microscopic Calcium Signaling by Pixel-Wise Fitting

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