The Experts below are selected from a list of 282 Experts worldwide ranked by ideXlab platform
Adam S. Helms - One of the best experts on this subject based on the ideXlab platform.
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Myofibrillar Structural Variability Underlies Contractile Function in Stem Cell-Derived Cardiomyocytes.
Stem cell reports, 2021Co-Authors: Kathryn Ufford, Sabrina Friedline, Zhaowen Tong, Vi T. Tang, Amani S. Dobbs, Yao-chang Tsan, Stephanie L. Bielas, Allen P. Liu, Adam S. HelmsAbstract:Disease modeling and pharmaceutical testing using cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) requires accurate assessment of Contractile Function. Micropatterning iPSC-CMs on elastic substrates controls cell shape and alignment to enable Contractile studies, but determinants of intrinsic variability in this system have been incompletely characterized. The objective of this study was to determine the impact of myofibrillar structure on Contractile Function in iPSC-CMs. Automated analysis of micropatterned iPSC-CMs labeled with a cell-permeant F-actin dye revealed that myofibrillar abundance is widely variable among iPSC-CMs and strongly correlates with Contractile Function. This variability is not reduced by subcloning from single iPSCs and is independent of the iPSC-CM purification method. Controlling for myofibrillar structure reduces false-positive findings related to batch effect and improves sensitivity for pharmacologic testing and disease modeling. This analysis provides compelling evidence that myofibrillar structure should be assessed concurrently in studies investigating Contractile Function in iPSC-CMs.
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Myofibrillar Structural Variability Underlies Contractile Function in Stem Cell-Derived Cardiomyocytes
2020Co-Authors: Kathryn Ufford, Sabrina Friedline, Zhaowen Tong, Vi T. Tang, Amani S. Dobbs, Yao-chang Tsan, Stephanie L. Bielas, Allen P. Liu, Adam S. HelmsAbstract:Disease modeling and pharmaceutical testing using cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) requires accurate assessment of Contractile Function. Micropatterning iPSC-CMs on elastic substrates controls cell shape and alignment to enable Contractile studies, but the determinants of intrinsic variability in this system have been incompletely characterized. The primary objective of this study was to determine the impact of myofibrillar structure on Contractile Function in iPSC-CMs. After labeling micropatterned iPSC-CMs with a cell permeant F-actin dye, we imaged both myofibrillar structure and Contractile Function. Using automated myofibrillar image analysis, we demonstrate that myofibrillar abundance is widely variable among individual iPSC-CMs and strongly correlates with Contractile Function. This variability is not reduced by subcloning from single iPSCs to reduce genetic heterogeneity, persists with two different iPSC-CM purification methods, and similarly is present for embryonic stem cell-derived cardiomyocytes. This analysis provides compelling evidence that myofibrillar structure should be quantified and controlled for in studies investigating Contractile Function in iPSC-CMs.
Kathryn Ufford - One of the best experts on this subject based on the ideXlab platform.
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Myofibrillar Structural Variability Underlies Contractile Function in Stem Cell-Derived Cardiomyocytes.
Stem cell reports, 2021Co-Authors: Kathryn Ufford, Sabrina Friedline, Zhaowen Tong, Vi T. Tang, Amani S. Dobbs, Yao-chang Tsan, Stephanie L. Bielas, Allen P. Liu, Adam S. HelmsAbstract:Disease modeling and pharmaceutical testing using cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) requires accurate assessment of Contractile Function. Micropatterning iPSC-CMs on elastic substrates controls cell shape and alignment to enable Contractile studies, but determinants of intrinsic variability in this system have been incompletely characterized. The objective of this study was to determine the impact of myofibrillar structure on Contractile Function in iPSC-CMs. Automated analysis of micropatterned iPSC-CMs labeled with a cell-permeant F-actin dye revealed that myofibrillar abundance is widely variable among iPSC-CMs and strongly correlates with Contractile Function. This variability is not reduced by subcloning from single iPSCs and is independent of the iPSC-CM purification method. Controlling for myofibrillar structure reduces false-positive findings related to batch effect and improves sensitivity for pharmacologic testing and disease modeling. This analysis provides compelling evidence that myofibrillar structure should be assessed concurrently in studies investigating Contractile Function in iPSC-CMs.
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Myofibrillar Structural Variability Underlies Contractile Function in Stem Cell-Derived Cardiomyocytes
2020Co-Authors: Kathryn Ufford, Sabrina Friedline, Zhaowen Tong, Vi T. Tang, Amani S. Dobbs, Yao-chang Tsan, Stephanie L. Bielas, Allen P. Liu, Adam S. HelmsAbstract:Disease modeling and pharmaceutical testing using cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) requires accurate assessment of Contractile Function. Micropatterning iPSC-CMs on elastic substrates controls cell shape and alignment to enable Contractile studies, but the determinants of intrinsic variability in this system have been incompletely characterized. The primary objective of this study was to determine the impact of myofibrillar structure on Contractile Function in iPSC-CMs. After labeling micropatterned iPSC-CMs with a cell permeant F-actin dye, we imaged both myofibrillar structure and Contractile Function. Using automated myofibrillar image analysis, we demonstrate that myofibrillar abundance is widely variable among individual iPSC-CMs and strongly correlates with Contractile Function. This variability is not reduced by subcloning from single iPSCs to reduce genetic heterogeneity, persists with two different iPSC-CM purification methods, and similarly is present for embryonic stem cell-derived cardiomyocytes. This analysis provides compelling evidence that myofibrillar structure should be quantified and controlled for in studies investigating Contractile Function in iPSC-CMs.
Frank Seebacher - One of the best experts on this subject based on the ideXlab platform.
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the effects of obesity on skeletal muscle Contractile Function
The Journal of Experimental Biology, 2018Co-Authors: Jason Tallis, Rob S James, Frank SeebacherAbstract:Obesity can cause a decline in Contractile Function of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks. We reviewed the literature to establish the current state-of-knowledge of how obesity affects skeletal muscle contraction and relaxation. At a cellular level, the dominant effects of obesity are disrupted calcium signalling and 5'-adenosine monophosphate-activated protein kinase (AMPK) activity. As a result, there is a shift from slow to fast muscle fibre types. Decreased AMPK activity promotes the class II histone deacetylase (HDAC)-mediated inhibition of the myocyte enhancer factor 2 (MEF2). MEF2 promotes slow fibre type expression, and its activity is stimulated by the calcium-dependent phosphatase calcineurin. Obesity-induced attenuation of calcium signalling via its effects on calcineurin, as well as on adiponectin and actinin affects excitation-contraction coupling and excitation-transcription coupling in the myocyte. These molecular changes affect muscle Contractile Function and phenotype, and thereby in vivo and in vitro muscle performance. In vivo, obesity can increase the absolute force and power produced by increasing the demand on weight-supporting muscle. However, when normalised to body mass, muscle performance of obese individuals is reduced. Isolated muscle preparations show that obesity often leads to a decrease in force produced per muscle cross-sectional area, and power produced per muscle mass. Obesity and ageing have similar physiological consequences. The synergistic effects of obesity and ageing on muscle Function may exacerbate morbidity and mortality. Important future research directions include determining: the relationship between time course of weight gain and changes in muscle Function; the relative effects of weight gain and high-fat diet feeding per se; the effects of obesity on muscle Function during ageing; and if the effects of obesity on muscle Function are reversible.
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Skeletal muscle Contractile Function predicts activity and behaviour in zebrafish.
Journal of Experimental Biology, 2015Co-Authors: Frank Seebacher, Alexander G. Little, Rob S JamesAbstract:Locomotion facilitates behaviour and its underlying physiological mechanisms may therefore impact behavioural phenotypes. Metabolism is often thought to modulate locomotion and behaviour, but empirical support for this suggestion is equivocal. Muscle Contractile Function is directly associated with locomotion. Here, we test the hypotheses that muscle mechanics determine locomotor performance and activity in zebrafish (Danio rerio) and thereby also affect risk-taking behaviour. We show that there is a mechanistic link between muscle performance and behaviour by manipulating muscle Contractile properties, which caused proportional changes in critical sustained swimming performance and, in an open arena, voluntary swimming speed, the proportion of time fish were active, and the latency to move. We modelled the relationships between muscle Contractile properties, swimming performance, activity and behaviour with a partial least-squares path model. The latent variable 'muscle', formed by isolated muscle force production, stress, fatigue resistance and activation and relaxation rates, had a significant positive effect on swimming performance ('swim' reflected in sustained and sprint speeds). Together, muscle and swim had a significant positive effect on activity, and explained 71.8% of variation in the distance moved, time active and maximum voluntary speed in an open field. Activity had a significant positive effect on boldness, explaining 76.0% of variation in latencies to move and to approach a novel object. Muscle Contractile Function determines voluntary movement and we suggest that exploration and dispersal are Functions of physiological and mechanical optimisation. Boldness therefore may be partly explained by the greater likelihood of faster fish to move further and encounter novel objects and conspecifics more quickly as a result.
Francis G. Spinale - One of the best experts on this subject based on the ideXlab platform.
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The direct effects of propofol on myocyte Contractile Function after hypothermic cardioplegic arrest.
Anesthesia and analgesia, 1996Co-Authors: Latha Hebbar, B. H. Dorman, Raymond C. Roy, Francis G. SpinaleAbstract:Propofol is being used more often in cardiac surgery, particularly after hypothermic, hyperkalemic cardioplegic arrest (HHCA). The purpose of this study was to examine the effects of propofol on isolated myocyte Contractile Function under both normothermic conditions and after simulated HHCA and rewarming. Myocytes were isolated from the left ventricle of eight pigs. Myocyte Contractile Function was measured under both normothermic conditions and after simulated HHCA (incubation at 4 degrees C for 2 h in crystalloid cardioplegia; K+ = 24 mEq/L) using computer-assisted videomicroscopy in the presence of 2, 4, and 6 micrograms/mL propofol (11.2, 22.4, and 33.6 microM/L, respectively). Isoproterenol (25 nM) was then added and Contractile Function measurements repeated. Propofol caused significant dose-dependent reductions in myocyte velocity of shortening (baseline = 67 +/- 2 microns/s; propofol = 2 micrograms/mL, 45 +/- 4 microns/s; and propofol = 6 micrograms/mL, 27 +/- 3 microns/s; P < 0.05). HHCA and rewarming caused a significant reduction in myocyte velocity of shortening (29 +/- 0.9 microns/s, P < 0.05), with further significant dose-dependent reductions in Contractile Function after the addition of propofol. Propofol caused a decrease in beta-adrenergic responsiveness under normothermic conditions, but not after simulated HHCA. Results from the present study demonstrated for the first time that the reduction in isolated myocyte Contractile Function after simulated HHCA is further decreased by propofol administration.
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Differential effects of protamine sulfate on myocyte Contractile Function with left ventricular failure
Journal of the American College of Cardiology, 1995Co-Authors: R. Barry Hird, Fred A Crawford, Francis G. SpinaleAbstract:Objectives. This project tested two fundamental hypotheses: 1) Protamine sulfate has a direct and negative effect on myocyte Contractile processes; 2) the negative effects of protamine on myocyte contractility will be enhanced in the setting of chronic left ventricular dysFunction. Background. An increasing number of patients undergoing cardiac and vascular surgical procedures have underlying chronic left ventricular dysFunction. Protamine sulfate is commonly required during these surgical procedures but has been associated with left ventricular dysFunction. However, it is not known whether protamine may have a direct and selective effect on myocyte contractility in the setting of chronic left ventricular dysFunction. Methods. This study examined the direct effects of protamine on isolated myocyte Contractile Function in 10 control pigs and 10 pigs with dilated cardiomyopathy induced by supraventricular tachycardia (rapid atrial pacing at 240 beats/min for 3 weeks). Myocyte Contractile Function was measured by videomicroscopy at baseline and with 10, 20, 40 or 80 μ g/ml of protamine. In a second series of experiments, myocytes were preincubated with protamine and then stimulated with the beta-adrenergic agonist isoproterenol (25 nmol/liter). Results. In the presence of 20 μ g/ml of protamine, myocyte Contractile Function was unaffected in the control group but decreased by 40% from baseline values in the supraventricular tachycardia group. With 10 μ g/ml of protamine, myocyte betaadrenergic responsiveness was reduced by 25% in the supraventricular tachycardia group with no change in the control group. In the presence of 40 and 80 μ g/ml of protamine, myocyte Contractile Function decreased in both groups. However, 40 μ g/ml of protamine caused a more pronounced decline in myocyte Function and beta-adrenergic responsiveness in the supraventricular tachycardia group. Conclusions. An increased sensitivity to the depressive effects of protamine on myocyte Contractile Function and beta-adrenergic responsiveness occurred in this model of chronic left ventricular dysFunction. These results suggest that patients with underlying cardiac disease may have an increased susceptibility to a sudden compromise of left ventricular Contractile performance after protamine administration.
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Direct effects of thrombin on myocyte Contractile Function.
The Annals of Thoracic Surgery, 1995Co-Authors: R. Barry Hird, Francis G. Spinale, Rupak Mukherjee, Fred A Crawford, Francis G. SpinaleAbstract:Cardiopulmonary bypass activates the clotting cascade, resulting in elevated circulating levels of thrombin. In light of the fact that the Function of a wide variety of cell types is modulated by thrombin, we hypothesized that thrombin may have a direct effect on myocyte Function. Isolated left ventricular myocyte Contractile Function was measured from 6 adult dogs using videomicroscopy at baseline and after increasing concentrations of thrombin (1 to 10 U/mL). Indices of myocyte Contractile Function were reduced in a dose-dependent manner in the presence of increasing concentrations of thrombin. For example, myocyte percent shortening fell by 18% with 1 U/mL thrombin and by 43% with 2 U/mL thrombin. The addition of hirudin, a highly selective thrombin inhibitor, completely blocked the effects of thrombin on myocyte Contractile Function. β -Adrenergic agonists are commonly used in the early post—cardiopulmonary bypass period. Accordingly, a final set of experiments examined the effects of thrombin on myocyte β -adrenergic responsiveness using isoproterenol (25 nmol/L). In myocytes preincubated with 1 U/mL thrombin, myocyte β -adrenergic responsiveness was significantly reduced. For example, in the presence of 1 U/mL thrombin, myocyte velocity of shortening fell by 25% from isoproterenol alone values. The results from the present study provide evidence that thrombin has a direct negative effect on steady-state Contractile Function and β -adrenergic responsiveness in adult mammalian ventricular myocytes. These findings suggest that thrombin may be an additional contributory factor toward the transient left ventricular dysFunction that has been observed after cardiopulmonary bypass.
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The direct and interactive effects of phosphodiesterase inhibition and beta-adrenergic stimulation on myocyte Contractile Function after hypothermic cardioplegic arrest.
Anesthesia and analgesia, 1995Co-Authors: B. H. Dorman, Raymond C. Roy, Martyn J. Cavallo, Francis G. SpinaleAbstract:The direct and interactive effects of phosphodiesterase inhibition (PDEI) and beta-adrenergic receptor (beta AR) stimulation on isolated myocyte Contractile Function were examined after hypothermic, hyperkalemic, cardioplegic arrest (HHCA) and under normothermic conditions. Left ventricular (LV) myocytes were isolated from porcine hearts and myocyte Contractile Function was measured under normothermic conditions (37 degrees C in standard media) and after HHCA (2 h at 4 degrees C in Ringer's solution with 24 mEq KCl) with subsequent rewarming. Myocytes were then randomly assigned to treatment with the beta AR agonist isoproterenol (25 nM), the phosphodiesterase inhibitor amrinone (50 microM), or a combination of these compounds and Contractile Function measurements repeated. Baseline myocyte Contractile Function was reduced by 32% after HHCA. Isoproternol alone increased myocyte Contractile Function more than 100% under both normothermic conditions and after HHCA, whereas amrinone alone significantly (60%) improved myocyte Contractile Function only after HHCA. Amrinone preincubation followed by isoproterenol improved Contractile Function after HHCA to a greater extent than all other treatment protocols. In contrast, combination treatment under normothermic conditions did not augment myocyte Contractile Function relative to isoproterenol alone. These findings suggest that amrinone has differential effects on Contractile processes. Moreover, the marked improvement of Contractile Function after HHCA with PDEI pretreatment followed by beta AR stimulation may have implications in treatment strategies for improving myocardial Function after cardiopulmonary bypass and provide insight into Contractile dysFunction after HHCA.
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Effects of protamine on myocyte Contractile Function and β-adrenergic responsiveness
The Annals of thoracic surgery, 1994Co-Authors: R. Barry Hird, Rupak Mukherjee, Fred A Crawford, Michael R. Zile, Francis G. SpinaleAbstract:Abstract The use of protamine sulfate in patients has been associated with severe circulatory collapse and myocardial failure. However, the exact mechanisms responsible for these reactions to protamine remain unclear. Accordingly, we examined the effect of protamine on isolated myocyte Contractile Function. Indexes of isolated myocyte Contractile Function, percent shortening, and velocity of shortening were examined using videomicroscopy. Porcine cardiocytes (n = 75) were studied at baseline and in the presence of 80 μg/mL protamine. In addition, myocyte Function was examined sequentially, first during treatment with 8 IU/mL heparin and then after the addition of a protamine dose sufficient to completely bind the heparin. The binding of heparin and protamine resulted in the formation of a heparin-ptotamine complex. The protamine concentration of 80 μg/mL is approximately equal to the serum concentration of protamine obtained in patients when administered in a dose of 5 mg/kg. In the presence of 80 μg/mL protamine, both percent shortening and velocity of shortening fell by more than 32% from baseline values ( p
Amani S. Dobbs - One of the best experts on this subject based on the ideXlab platform.
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Myofibrillar Structural Variability Underlies Contractile Function in Stem Cell-Derived Cardiomyocytes.
Stem cell reports, 2021Co-Authors: Kathryn Ufford, Sabrina Friedline, Zhaowen Tong, Vi T. Tang, Amani S. Dobbs, Yao-chang Tsan, Stephanie L. Bielas, Allen P. Liu, Adam S. HelmsAbstract:Disease modeling and pharmaceutical testing using cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) requires accurate assessment of Contractile Function. Micropatterning iPSC-CMs on elastic substrates controls cell shape and alignment to enable Contractile studies, but determinants of intrinsic variability in this system have been incompletely characterized. The objective of this study was to determine the impact of myofibrillar structure on Contractile Function in iPSC-CMs. Automated analysis of micropatterned iPSC-CMs labeled with a cell-permeant F-actin dye revealed that myofibrillar abundance is widely variable among iPSC-CMs and strongly correlates with Contractile Function. This variability is not reduced by subcloning from single iPSCs and is independent of the iPSC-CM purification method. Controlling for myofibrillar structure reduces false-positive findings related to batch effect and improves sensitivity for pharmacologic testing and disease modeling. This analysis provides compelling evidence that myofibrillar structure should be assessed concurrently in studies investigating Contractile Function in iPSC-CMs.
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Myofibrillar Structural Variability Underlies Contractile Function in Stem Cell-Derived Cardiomyocytes
2020Co-Authors: Kathryn Ufford, Sabrina Friedline, Zhaowen Tong, Vi T. Tang, Amani S. Dobbs, Yao-chang Tsan, Stephanie L. Bielas, Allen P. Liu, Adam S. HelmsAbstract:Disease modeling and pharmaceutical testing using cardiomyocytes derived from induced pluripotent stem cell (iPSC-CMs) requires accurate assessment of Contractile Function. Micropatterning iPSC-CMs on elastic substrates controls cell shape and alignment to enable Contractile studies, but the determinants of intrinsic variability in this system have been incompletely characterized. The primary objective of this study was to determine the impact of myofibrillar structure on Contractile Function in iPSC-CMs. After labeling micropatterned iPSC-CMs with a cell permeant F-actin dye, we imaged both myofibrillar structure and Contractile Function. Using automated myofibrillar image analysis, we demonstrate that myofibrillar abundance is widely variable among individual iPSC-CMs and strongly correlates with Contractile Function. This variability is not reduced by subcloning from single iPSCs to reduce genetic heterogeneity, persists with two different iPSC-CM purification methods, and similarly is present for embryonic stem cell-derived cardiomyocytes. This analysis provides compelling evidence that myofibrillar structure should be quantified and controlled for in studies investigating Contractile Function in iPSC-CMs.