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Valdur Saks - One of the best experts on this subject based on the ideXlab platform.
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Intracellular Energetic Units regulate metabolism in cardiac cells.
Journal of Molecular and Cellular Cardiology, 2011Co-Authors: Valdur Saks, Andrey Kuznetsov, Marcela Gonzalez-granillo, Kersti Tepp, Natalja Timohhina, Minna Karu-varikmaa, Tuuli Kaambre, Pierre Dos Santos, François Boucher, Rita GuzunAbstract:This review describes developments in historical perspective as well as recent results of investigations of cellular mechanisms of regulation of energy fluxes and mitochondrial respiration by cardiac work - the metabolic aspect of the Frank-Starling Law of the heart. A Systems Biology solution to this problem needs the integration of physiological and biochemical mechanisms that take into account intracellular interactions of mitochondria with other cellular systems, in particular with cytoskeleton components. Recent data show that different tubulin isotypes are involved in the regular arrangement exhibited by mitochondria and ATP-consuming systems into Intracellular Energetic Units (ICEUs). Beta II tubulin association with the mitochondrial outer membrane, when co-expressed with mitochondrial creatine kinase (MtCK) specifically limits the permeability of voltage-dependent anion channel for adenine nucleotides. In the MtCK reaction this interaction changes the regulatory kinetics of respiration through a decrease in the affinity for adenine nucleotides and an increase in the affinity for creatine. Metabolic Control Analysis of the coupled MtCK-ATP Synthasome in permeabilized cardiomyocytes showed a significant increase in flux control by steps involved in ADP recycling. Mathematical modeling of compartmentalized energy transfer represented by ICEUs shows that cyclic changes in local ADP, Pi, phosphocreatine and creatine concentrations during contraction cycle represent effective metabolic feedback signals when amplified in the coupled non-equilibrium MtCK-ATP Synthasome reactions in mitochondria. This mechanism explains the regulation of respiration on beat to beat basis during workload changes under conditions of metabolic stability. This article is part of a Special Issue entitled Local Signaling in Myocytes SI.
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Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function
Amino Acids, 2011Co-Authors: Rita Guzun, N. Timohhina, K. Tepp, M. Gonzalez-granillo, I. Shevchuk, V. Chekulayev, A. V. Kuznetsov, T. Kaambre, Valdur SaksAbstract:Physiological role of creatine (Cr) became first evident in the experiments of Belitzer and Tsybakova in 1939, who showed that oxygen consumption in a well-washed skeletal muscle homogenate increases strongly in the presence of creatine and with this results in phosphocreatine (PCr) production with PCr/O_2 ratio of about 5–6. This was the beginning of quantitative analysis in bioenergetics. It was also observed in many physiological experiments that the contractile force changes in parallel with the alteration in the PCr content. On the other hand, it was shown that when heart function is governed by Frank–Starling Law, work performance and oxygen consumption rate increase in parallel without any changes in PCr and ATP tissue contents (metabolic homeostasis). Studies of cellular mechanisms of all these important phenomena helped in shaping new approach to bioenergetics, Molecular System Bioenergetics, a part of Systems Biology. This approach takes into consideration intracellular interactions that lead to novel mechanisms of regulation of energy fluxes. In particular, interactions between mitochondria and cytoskeleton resulting in selective restriction of permeability of outer mitochondrial membrane anion channel (VDAC) for adenine nucleotides and thus their recycling in mitochondria coupled to effective synthesis of PCr by mitochondrial creatine kinase, MtCK. Therefore, Cr concentration and the PCr/Cr ratio became important kinetic parameters in the regulation of respiration and energy fluxes in muscle cells. Decrease in the intracellular contents of Cr and PCr results in a hypodynamic state of muscle and muscle pathology. Many experimental studies have revealed that PCr may play two important roles in the regulation of muscle energetics: first by maintaining local ATP pools via compartmentalized creatine kinase reactions, and secondly by stabilizing cellular membranes due to electrostatic interactions with phospholipids. The second mechanism decreases the production of lysophosphoglycerides in hypoxic heart, protects the cardiac cells sarcolemma against ischemic damage, decreases the frequency of arrhythmias and increases the post-ischemic recovery of contractile function. PCr is used as a pharmacological product Neoton in cardiac surgery as one of the components of cardioplegic solutions for protection of the heart against intraoperational injury and injected intravenously in acute myocardial ischemic conditions for improving the hemodynamic response and clinical conditions of patients with heart failure.
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Application of the principles of systems biology and Wiener's cybernetics for analysis of regulation of energy fluxes in muscle cells in vivo
International Journal of Molecular Sciences, 2010Co-Authors: Rita Guzun, Valdur SaksAbstract:The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener's cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by the Frank-Starling Law and the main metabolic characteristic of cardiac muscle cells is metabolic homeostasis, when both workload and respiration rate can be changed manifold at constant intracellular level of phosphocreatine and ATP in the cells. This is not observed in skeletal muscles. Controversies in theoretical explanations of these observations are analyzed. Experimental studies of permeabilized fibers from human skeletal muscle vastus lateralis and adult rat cardiomyocytes showed that the respiration rate is always an apparent hyperbolic but not a sigmoid function of ADP concentration. It is our conclusion that realistic explanations of regulation of energy fluxes in muscle cells require systemic approaches including application of the feedback theory of Wiener's cybernetics in combination with detailed experimental research. Such an analysis reveals the importance of limited permeability of mitochondrial outer membrane for ADP due to interactions of mitochondria with cytoskeleton resulting in quasi-linear dependence of respiration rate on amplitude of cyclic changes in cytoplasmic ADP concentrations. The system of compartmentalized creatine kinase (CK) isoenzymes functionally coupled to ANT and ATPases, and mitochondrial-cytoskeletal interactions separate energy fluxes (mass and energy transfer) from signalling (information transfer) within dissipative metabolic structures - intracellular energetic units (ICEU). Due to the non-equilibrium state of CK reactions, intracellular ATP utilization and mitochondrial ATP regeneration are interconnected by the PCr flux from mitochondria. The feedback regulation of respiration occurring via cyclic fluctuations of cytosolic ADP, Pi and Cr/PCr ensures metabolic stability necessary for normal function of cardiac cells.
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Cardiac system bioenergetics: metabolic basis of the Frank‐Starling Law
The Journal of Physiology, 2006Co-Authors: Valdur Saks, Petras Dzeja, Uwe Schlattner, Marko Vendelin, Andre Terzic, Theo WallimannAbstract:The fundamental principle of cardiac behaviour is described by the Frank-Starling Law relating force of contraction during systole with end-diastolic volume. While both work and respiration rates increase linearly with imposed load, the basis of mechano-energetic coupling in heart muscle has remained a long-standing enigma. Here, we highlight advances made in understanding of complex cellular and molecular mechanisms that orchestrate coupling of mitochondrial oxidative phosphorylation with ATP utilization for muscle contraction. Cardiac system bioenergetics critically depends on an interrelated metabolic infrastructure regulating mitochondrial respiration and energy fluxes throughout cellular compartments. The data reviewed indicate the significance of two interrelated systems regulating mitochondrial respiration and energy fluxes in cells: (1) the creatine kinase, adenylate kinase and glycolytic pathways that communicate flux changes generated by cellular ATPases within structurally organized enzymatic modules and networks; and (2) a secondary system based on mitochondrial participation in cellular calcium cycle, which adjusts substrate oxidation and energy-transducing processes to meet increasing cellular energy demands. By conveying energetic signals to metabolic sensors, coupled phosphotransfer reactions provide a high-fidelity regulation of the excitation–contraction cycle. Such integration of energetics with calcium signalling systems provides the basis for ‘metabolic pacing’, synchronizing the cellular electrical and mechanical activities with energy supply processes.
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Cardiac system bioenergetics: metabolic basis of the Frank-Starling Law.
The Journal of physiology, 2006Co-Authors: Valdur Saks, Petras Dzeja, Uwe Schlattner, Marko Vendelin, Andre Terzic, Theo WallimannAbstract:The fundamental principle of cardiac behaviour is described by the Frank-Starling Law relating force of contraction during systole with end-diastolic volume. While both work and respiration rates increase linearly with imposed load, the basis of mechano-energetic coupling in heart muscle has remained a long-standing enigma. Here, we highlight advances made in understanding of complex cellular and molecular mechanisms that orchestrate coupling of mitochondrial oxidative phosphorylation with ATP utilization for muscle contraction. Cardiac system bioenergetics critically depends on an interrelated metabolic infrastructure regulating mitochondrial respiration and energy fluxes throughout cellular compartments. The data reviewed indicate the significance of two interrelated systems regulating mitochondrial respiration and energy fluxes in cells: (1) the creatine kinase, adenylate kinase and glycolytic pathways that communicate flux changes generated by cellular ATPases within structurally organized enzymatic modules and networks; and (2) a secondary system based on mitochondrial participation in cellular calcium cycle, which adjusts substrate oxidation and energy-transducing processes to meet increasing cellular energy demands. By conveying energetic signals to metabolic sensors, coupled phosphotransfer reactions provide a high-fidelity regulation of the excitation-contraction cycle. Such integration of energetics with calcium signalling systems provides the basis for 'metabolic pacing', synchronizing the cellular electrical and mechanical activities with energy supply processes.
Pieter P De Tombe - One of the best experts on this subject based on the ideXlab platform.
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titin strain contributes to the frank Starling Law of the heart by structural rearrangements of both thin and thick filament proteins
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Younss Aitmou, Gerrie P Farman, Thomas C Irving, Karen Hsu, Mohit Kumar, Marion L Greaser, Pieter P De TombeAbstract:The Frank-Starling mechanism of the heart is due, in part, to modulation of myofilament Ca(2+) sensitivity by sarcomere length (SL) [length-dependent activation (LDA)]. The molecular mechanism(s) that underlie LDA are unknown. Recent evidence has implicated the giant protein titin in this cellular process, possibly by positioning the myosin head closer to actin. To clarify the role of titin strain in LDA, we isolated myocardium from either WT or homozygous mutant (HM) rats that express a giant splice isoform of titin, and subjected the muscles to stretch from 2.0 to 2.4 μm of SL. Upon stretch, HM compared with WT muscles displayed reduced passive force, twitch force, and myofilament LDA. Time-resolved small-angle X-ray diffraction measurements of WT twitching muscles during diastole revealed stretch-induced increases in the intensity of myosin (M2 and M6) and troponin (Tn3) reflections, as well as a reduction in cross-bridge radial spacing. Independent fluorescent probe analyses in relaxed permeabilized myocytes corroborated these findings. X-ray electron density reconstruction revealed increased mass/ordering in both thick and thin filaments. The SL-dependent changes in structure observed in WT myocardium were absent in HM myocardium. Overall, our results reveal a correlation between titin strain and the Frank-Starling mechanism. The molecular basis underlying this phenomenon appears not to involve interfilament spacing or movement of myosin toward actin but, rather, sarcomere stretch-induced simultaneous structural rearrangements within both thin and thick filaments that correlate with titin strain and myofilament LDA.
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myosin head orientation a structural determinant for the frank Starling relationship
American Journal of Physiology-heart and Circulatory Physiology, 2011Co-Authors: Gerrie P Farman, David Gore, Edward Allen, Kelly Schoenfelt, Thomas C Irving, Pieter P De TombeAbstract:The cellular mechanism underlying the Frank-Starling Law of the heart is myofilament length-dependent activation. The mechanism(s) whereby sarcomeres detect changes in length and translate this int...
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Radial Motion of Myosin Heads in Isolated Intact Rat Myocardium in Diastole
Biophysical Journal, 2011Co-Authors: Gerrie P Farman, David Gore, Edward Allen, Thomas C Irving, Kelly Q. Schoenfelt, Pieter P De TombeAbstract:The main cellular mechanism that underlies the so-called “Frank -Starling Law of the Heart” is an increase in the responsiveness of cardiac myofilaments to activating Ca2+ ions at longer sarcomere lengths (SL). The fundamental mechanism responsible for this increase in responsiveness has been elusive, despite considerable experimental scrutiny. Here we tested the hypothesis that the increase in calcium sensitivity upon increasing SL is correlated with a radially outward movement of the myosin heads during diastole. 2D x-ray diffraction patterns were obtained from electrically stimulated intact, twitching papillary muscle isolated from rat hearts during a 10 ms time window in diastole just prior to electrical stimulation. A range of sarcomere lengths was compared either at Lmax (SL= ∼2.3 µm) or following a quick release to slack length (SL=∼1.9µm). The relative position of myosin heads was first assessed by the I11/I10 equatorial intensity ratio. To our surprise, I 11/I10 was negatively correlated with SL, i.e. I11/I10 was less at Lmax vs. slack length. A more direct measure of the radial position of the myosin heads can be estimated from the position of the first maxima on the unsampled myosin layer lines, which are prominent in diastole. The intensity maxima, when examined pair-wise, moved outwards to a maximum of 5-6% for a 0.4µm change in SL indicating that the heads must be moving radially outward at slack length. Our data suggest that myofilament length dependent activation does not derive from a radial extension of the myosin heads at the long SL and must, therefore, involve some other mechanism. Supported by NIH HL75494 and RR08630.
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Myofilament length dependent activation
Journal of Molecular and Cellular Cardiology, 2010Co-Authors: Pieter P De Tombe, Gerrie P Farman, Ryan D. Mateja, Kittipong Tachampa, Younss Ait Mou, Thomas C IrvingAbstract:Abstract The Frank–Starling Law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a beat-to-beat basis. The main cellular mechanism that underlies this phenomenon is an increase in the responsiveness of cardiac myofilaments to activating Ca2+ ions at a longer sarcomere length, commonly referred to as myofilament length-dependent activation. This review focuses on what molecular mechanisms may underlie myofilament length dependency. Specifically, the roles of inter-filament spacing, thick and thin filament based regulation, as well as sarcomeric regulatory proteins are discussed. Although the “Frank–Starling Law of the heart” constitutes a fundamental cardiac property that has been appreciated for well over a century, it is still not known in muscle how the contractile apparatus transduces the information concerning sarcomere length to modulate ventricular pressure development.
Rita Guzun - One of the best experts on this subject based on the ideXlab platform.
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Intracellular Energetic Units regulate metabolism in cardiac cells.
Journal of Molecular and Cellular Cardiology, 2011Co-Authors: Valdur Saks, Andrey Kuznetsov, Marcela Gonzalez-granillo, Kersti Tepp, Natalja Timohhina, Minna Karu-varikmaa, Tuuli Kaambre, Pierre Dos Santos, François Boucher, Rita GuzunAbstract:This review describes developments in historical perspective as well as recent results of investigations of cellular mechanisms of regulation of energy fluxes and mitochondrial respiration by cardiac work - the metabolic aspect of the Frank-Starling Law of the heart. A Systems Biology solution to this problem needs the integration of physiological and biochemical mechanisms that take into account intracellular interactions of mitochondria with other cellular systems, in particular with cytoskeleton components. Recent data show that different tubulin isotypes are involved in the regular arrangement exhibited by mitochondria and ATP-consuming systems into Intracellular Energetic Units (ICEUs). Beta II tubulin association with the mitochondrial outer membrane, when co-expressed with mitochondrial creatine kinase (MtCK) specifically limits the permeability of voltage-dependent anion channel for adenine nucleotides. In the MtCK reaction this interaction changes the regulatory kinetics of respiration through a decrease in the affinity for adenine nucleotides and an increase in the affinity for creatine. Metabolic Control Analysis of the coupled MtCK-ATP Synthasome in permeabilized cardiomyocytes showed a significant increase in flux control by steps involved in ADP recycling. Mathematical modeling of compartmentalized energy transfer represented by ICEUs shows that cyclic changes in local ADP, Pi, phosphocreatine and creatine concentrations during contraction cycle represent effective metabolic feedback signals when amplified in the coupled non-equilibrium MtCK-ATP Synthasome reactions in mitochondria. This mechanism explains the regulation of respiration on beat to beat basis during workload changes under conditions of metabolic stability. This article is part of a Special Issue entitled Local Signaling in Myocytes SI.
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Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function
Amino Acids, 2011Co-Authors: Rita Guzun, N. Timohhina, K. Tepp, M. Gonzalez-granillo, I. Shevchuk, V. Chekulayev, A. V. Kuznetsov, T. Kaambre, Valdur SaksAbstract:Physiological role of creatine (Cr) became first evident in the experiments of Belitzer and Tsybakova in 1939, who showed that oxygen consumption in a well-washed skeletal muscle homogenate increases strongly in the presence of creatine and with this results in phosphocreatine (PCr) production with PCr/O_2 ratio of about 5–6. This was the beginning of quantitative analysis in bioenergetics. It was also observed in many physiological experiments that the contractile force changes in parallel with the alteration in the PCr content. On the other hand, it was shown that when heart function is governed by Frank–Starling Law, work performance and oxygen consumption rate increase in parallel without any changes in PCr and ATP tissue contents (metabolic homeostasis). Studies of cellular mechanisms of all these important phenomena helped in shaping new approach to bioenergetics, Molecular System Bioenergetics, a part of Systems Biology. This approach takes into consideration intracellular interactions that lead to novel mechanisms of regulation of energy fluxes. In particular, interactions between mitochondria and cytoskeleton resulting in selective restriction of permeability of outer mitochondrial membrane anion channel (VDAC) for adenine nucleotides and thus their recycling in mitochondria coupled to effective synthesis of PCr by mitochondrial creatine kinase, MtCK. Therefore, Cr concentration and the PCr/Cr ratio became important kinetic parameters in the regulation of respiration and energy fluxes in muscle cells. Decrease in the intracellular contents of Cr and PCr results in a hypodynamic state of muscle and muscle pathology. Many experimental studies have revealed that PCr may play two important roles in the regulation of muscle energetics: first by maintaining local ATP pools via compartmentalized creatine kinase reactions, and secondly by stabilizing cellular membranes due to electrostatic interactions with phospholipids. The second mechanism decreases the production of lysophosphoglycerides in hypoxic heart, protects the cardiac cells sarcolemma against ischemic damage, decreases the frequency of arrhythmias and increases the post-ischemic recovery of contractile function. PCr is used as a pharmacological product Neoton in cardiac surgery as one of the components of cardioplegic solutions for protection of the heart against intraoperational injury and injected intravenously in acute myocardial ischemic conditions for improving the hemodynamic response and clinical conditions of patients with heart failure.
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Application of the principles of systems biology and Wiener's cybernetics for analysis of regulation of energy fluxes in muscle cells in vivo
International Journal of Molecular Sciences, 2010Co-Authors: Rita Guzun, Valdur SaksAbstract:The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener's cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by the Frank-Starling Law and the main metabolic characteristic of cardiac muscle cells is metabolic homeostasis, when both workload and respiration rate can be changed manifold at constant intracellular level of phosphocreatine and ATP in the cells. This is not observed in skeletal muscles. Controversies in theoretical explanations of these observations are analyzed. Experimental studies of permeabilized fibers from human skeletal muscle vastus lateralis and adult rat cardiomyocytes showed that the respiration rate is always an apparent hyperbolic but not a sigmoid function of ADP concentration. It is our conclusion that realistic explanations of regulation of energy fluxes in muscle cells require systemic approaches including application of the feedback theory of Wiener's cybernetics in combination with detailed experimental research. Such an analysis reveals the importance of limited permeability of mitochondrial outer membrane for ADP due to interactions of mitochondria with cytoskeleton resulting in quasi-linear dependence of respiration rate on amplitude of cyclic changes in cytoplasmic ADP concentrations. The system of compartmentalized creatine kinase (CK) isoenzymes functionally coupled to ANT and ATPases, and mitochondrial-cytoskeletal interactions separate energy fluxes (mass and energy transfer) from signalling (information transfer) within dissipative metabolic structures - intracellular energetic units (ICEU). Due to the non-equilibrium state of CK reactions, intracellular ATP utilization and mitochondrial ATP regeneration are interconnected by the PCr flux from mitochondria. The feedback regulation of respiration occurring via cyclic fluctuations of cytosolic ADP, Pi and Cr/PCr ensures metabolic stability necessary for normal function of cardiac cells.
Olivier Cazorla - One of the best experts on this subject based on the ideXlab platform.
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Regional variation in myofilament length-dependent activation.
Pflügers Archiv European Journal of Physiology, 2011Co-Authors: Olivier Cazorla, Alain LacampagneAbstract:The Frank-Starling Law is an important regulatory mechanism of the heart that links the end-diastolic volume with the systolic ejection fraction. This beat-to-beat regulation of the heart, underlined at the cellular level by higher myofilament calcium sensitivity at longer sarcomere length, is known as length-dependent activation or stretch sensitization of activation. However, the heart is structurally and functionally heterogeneous and asymmetrical. Specifically, contractile properties are not uniform within the left ventricle partly due to transmural differences in action potential waveforms and calcium homeostasis. The present review will focus on the role of the contractile machinery in the transmural contractile heterogeneity and its adaptation to changes in muscle strain. The expression of different myosin isoforms, the level of titin-based passive tension, and thin and thick sarcomeric regulatory proteins are considered to explain the regional cellular contractile properties. Finally, the importance of transmural heterogeneity of length-dependent activation and the consequences of its modification on the heart mechanics are discussed. Despite extensive research since the characterization of the Frank-Starling Law, the molecular mechanisms by which strain information is transduced to the contractile machinery have not been fully determined yet.
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Transmural stretch-dependent regulation of contractile properties in rat heart and its alteration after myocardial infarction
FASEB Journal, 2005Co-Authors: Olivier Cazorla, Szabolcs Szilagyi, Jean-yves Le Guennec, Guy Vassort, Alain LacampagneAbstract:The " stretch-sensitization " response is essential to the regulation of heart contractility. An increase in diastolic volume improves systolic contraction. The cellular mechanisms of this modulation, the Frank-Starling Law, are still uncertain. Moreover, their alterations in heart failure remains controversial. Here, using left ventricular skinned rat myocytes, we show a nonuniform stretch-sensitization of myofilament activation across the ventricular wall. Stretch-dependent Ca 2+ sensitization of myofilaments increases from sub-epicardium to sub-endocardium and is correlated with an increase in passive tension. This passive tension-dependent component of myofibrillar activation is not associated with expression of titin isoforms, changes in troponin I level, and phosphorylation status. Instead, we observe that stretch induces phosphorylation of ventricular myosin light chain 2 isoform (VLC2b) in sub-endocardium specifically. Thus, VLC2b phosphorylation could act as a stretch-dependent modulator of activation tuned within normal heart. Moreover, in postmyocardial infarcted rat, the gradient of stretch-dependent Ca 2+ sensitization disappears associated with a lack of VLC2b phosphorylation in sub-endocardium. In conclusion, nonuniformity is a major characteristic of the normal adult left ventricle (LV). The heterogeneous myocardial deformation pattern might be caused not only by the morphological heterogeneity of the tissue in the LV wall, but also by the nonuniform contractile properties of the myocytes across the wall. The loss of a contractile transmural gradient after myocardial infarction should contribute to the impaired LV function. Key words: Ca 2+ sensitization • Frank-Starling Law • ventricular myocytes • myosin light chain 2 • heart failure eart muscle has the property to develop positive inotropism in response to an increase in end-diastolic ventricular volume. This phenomenon, known as the Frank-Starling Law, originates from cell adaptation to stretch involving a sarcomere length (SL) dependence of the Ca 2+ sensitivity of myofilament activation (1). The mechanisms that underlie this intrinsic property may involve a length-dependent increase in the affinity of the regulatory site of troponin H
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Alteration of the Frank-Starling Law in heart failure relates to titin
Journal of Molecular and Cellular Cardiology, 2001Co-Authors: Olivier Cazorla, Alain Lacampagne, Harvard Viko, Claire Bony, Céline Cantos, J-yves Leguennec, Guy VassortAbstract:Alterations of the Frank-Starling relationship under pathological conditions is still a matter of controversy. We investigated this property in perfused whole hearts and in single cells isolated from normal and post-myocardium infarcted (PMI) rats. A balloon connected to a pressure sensor was implanted in the left ventricle, and the intraventricular pressure was monitored following changes in volume. A first group of rats with a very low level of remodeling had a preserved Frank-Starling relationship. The second group, in heart failure, was characterized by tremendous fibrosis and ventricle dilatation, and presented an alteration of the Frank-Starling relationship. ‘Ihe passive and contractile properties of single chemically skinned ventricular cells were measured as well as their length-dependent Ca2’ sensitivity. Cells from failing hearts exhibited a lower stiffness and abnormal tension-pCa properties characterized by a decrease (from 0.4 pCa Unit in control to below 0.2) in the shift of pCa50 induced by a stretch from 1.9 pm to 2.3 nm sarcomere length. Biochemical analysis of contractile proteins was performed. Polyacrylamide gel electrophoresis (2.5-12%) revealed an altered form of titin in the pathological conditions. Based on a previous report showing that the degradation of titin by a mild trypsin digestion resulted in an alteration of the contractility of normal cells (Cazorla et al. 1999), we conclude that the inability of failing hearts to use the Frank-Starling relationship is, in part, attributable to titin alteration.
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Length–Tension Relationships of Sub-epicardial and Sub-endocardial Single Ventricular Myocytes from Rat and Ferret Hearts
Journal of Molecular and Cellular Cardiology, 2000Co-Authors: Olivier Cazorla, Jean-yves Le Guennec, Ed WhiteAbstract:In vivo the sub-epicardial myocardium (EPI) and sub-endocardial myocardium (ENDO) operate over different ranges of sarcomere length (SL). However, it has not been previously shown whether EPI and ENDO work upon different ranges of the same or differing length–tension curves. We have compared the SL–tension relationship of intact, single ventricular EPI and ENDO myocytes from rat and ferret hearts. Cells were attached to carbon fibres of known compliance in order to stretch them and to record force at rest (passive tension) and during contractions (active tension). In both species, ENDO cells were significantly stiffer (i.e. had steeper SL–passive tension relationships) than EPI cells. Ferret ENDO cells had significantly steeper SL–active tension relationships than EPI cells; rat cells tended to behave similarly but no significant regional differences in active properties were observed. There were no inter-species differences in the active and passive properties of EPI cells, but ferret ENDO cells displayed significantly steeper passive and active SL–tension relationships than rat ENDO. We conclude that in vivo, ferret EPI and ENDO myocytes will function over different ranges of different SL–tension curves. There is a close relationship between SL and active tension (the Frank–Starling Law of the heart), and our observations suggest that regional differences in the response to ventricular dilation will depend on both the change in SL and differing regional slopes of the SL–active tension curves.
Nicolas P. Smith - One of the best experts on this subject based on the ideXlab platform.
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The Role of the Frank–Starling Law in the Transduction of Cellular Work to Whole Organ Pump Function: A Computational Modeling Analysis
PLoS Computational Biology, 2009Co-Authors: Steven Niederer, Nicolas P. SmithAbstract:We have developed a multi-scale biophysical electromechanics model of the rat left ventricle at room temperature. This model has been applied to investigate the relative roles of cellular scale length dependent regulators of tension generation on the transduction of work from the cell to whole organ pump function. Specifically, the role of the length dependent Ca2+ sensitivity of tension (Ca50), filament overlap tension dependence, velocity dependence of tension, and tension dependent binding of Ca2+ to Troponin C on metrics of efficient transduction of work and stress and strain homogeneity were predicted by performing simulations in the absence of each of these feedback mechanisms. The length dependent Ca50 and the filament overlap, which make up the Frank-Starling Law, were found to be the two dominant regulators of the efficient transduction of work. Analyzing the fiber velocity field in the absence of the Frank-Starling mechanisms showed that the decreased efficiency in the transduction of work in the absence of filament overlap effects was caused by increased post systolic shortening, whereas the decreased efficiency in the absence of length dependent Ca50 was caused by an inversion in the regional distribution of strain.
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the role of the frank Starling Law in the transduction of cellular work to whole organ pump function a computational modeling analysis
PLOS Computational Biology, 2009Co-Authors: Steven Niederer, Nicolas P. SmithAbstract:We have developed a multi-scale biophysical electromechanics model of the rat left ventricle at room temperature. This model has been applied to investigate the relative roles of cellular scale length dependent regulators of tension generation on the transduction of work from the cell to whole organ pump function. Specifically, the role of the length dependent Ca2+ sensitivity of tension (Ca50), filament overlap tension dependence, velocity dependence of tension, and tension dependent binding of Ca2+ to Troponin C on metrics of efficient transduction of work and stress and strain homogeneity were predicted by performing simulations in the absence of each of these feedback mechanisms. The length dependent Ca50 and the filament overlap, which make up the Frank-Starling Law, were found to be the two dominant regulators of the efficient transduction of work. Analyzing the fiber velocity field in the absence of the Frank-Starling mechanisms showed that the decreased efficiency in the transduction of work in the absence of filament overlap effects was caused by increased post systolic shortening, whereas the decreased efficiency in the absence of length dependent Ca50 was caused by an inversion in the regional distribution of strain.