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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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structural changes in both the troponin complex and the thick filament may underlie myofilament length dependent activation
Biophysical Journal, 2012Co-Authors: Hsiaoman Hsu, Thomas C Irving, Younss Ait Mou, 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+ at longer sarcomere lengths (SL). The structural basis of this “Length Dependent Activation” (LDA) is not known. 2D X-ray diffraction patterns were obtained using the BioCAT beamline 18ID at the Advanced Photon Source from electrically stimulated (0.2 Hz) intact, twitching papillary muscle isolated from rat hearts during a 10 ms time window in diastole just prior to electrical stimulation. Diffraction patterns were compared from muscles that were stretched to Lmax (SL= ∼2.3 μm) to those taken following a quick release to slack length (SL=∼1.9 μm). We previously reported that myosin heads moved radially inwards at longer SL suggesting that an increased radial extent of crossbridges at longer length cannot explain increased calcium sensitivity so other explanations must be sought. It is known that changes in isoform composition of the troponin complex can markedly affect calcium sensitivity but the role of troponin in the length sensing mechanism underlying LDA is not clear. Here we analyzed the meridional patterns which showed that the 3rd order troponin repeat distance, the 3rd - order troponin reflection intensity and the 2nd order myosin (“forbidden”) meridional reflection all increased significantly (P < 0.01) at Lmax as compared to slack length. Thus, stretching intact heart muscle in diastole induces changes in the structure of both the thick filaments and the thin filaments. It appears, then, that the length sensing mechanism underlying LDA must involve connections of some kind that transmit strain between the thick and thin filament that alter the structure of the troponin complex and, presumably, myofilament contractile properties. Supported by NIH HL075494 and RR08630.
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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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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.
Michael A Ferenczi - One of the best experts on this subject based on the ideXlab platform.
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revisiting frank starling regulatory light chain phosphorylation alters the rate of force redevelopment ktr in a length dependent fashion
The Journal of Physiology, 2016Co-Authors: Christopher N Toepfer, Timothy G West, Michael A FerencziAbstract:KEY POINTS Regulatory light chain (RLC) phosphorylation has been shown to alter the ability of muscle to produce force and power during shortening and to alter the rate of force redevelopment (ktr ) at submaximal [Ca(2+) ]. Increasing RLC phosphorylation ∼50% from the in vivo level in maximally [Ca(2+) ]-activated cardiac trabecula accelerates ktr . Decreasing RLC phosphorylation to ∼70% of the in vivo control level slows ktr and reduces force generation. ktr is dependent on sarcomere length in the physiological range 1.85-1.94 μm and RLC phosphorylation modulates this response. We demonstrate that Frank-Starling is evident at maximal [Ca(2+) ] activation and therefore does not necessarily require length-dependent change in [Ca(2+) ]-sensitivity of thin filament activation. The stretch response is modulated by changes in RLC phosphorylation, pinpointing RLC phosphorylation as a modulator of the Frank-Starling Law in the heart. These data provide an explanation for slowed systolic function in the intact heart in response to RLC phosphorylation reduction. ABSTRACT Force and power in cardiac muscle have a known dependence on phosphorylation of the myosin-associated regulatory light chain (RLC). We explore the effect of RLC phosphorylation on the ability of cardiac preparations to redevelop force (ktr ) in maximally activating [Ca(2+) ]. Activation was achieved by rapidly increasing the temperature (temperature-jump of 0.5-20oC) of permeabilized trabeculae over a physiological range of sarcomere lengths (1.85-1.94 μm). The trabeculae were subjected to shortening ramps over a range of velocities and the extent of RLC phosphorylation was varied. The latter was achieved using an RLC-exchange technique, which avoids changes in the phosphorylation level of other proteins. The results show that increasing RLC phosphorylation by 50% accelerates ktr by ∼50%, irrespective of the sarcomere length, whereas decreasing phosphorylation by 30% slows ktr by ∼50%, relative to the ktr obtained for in vivo phosphorylation. Clearly, phosphorylation affects the magnitude of ktr following step shortening or ramp shortening. Using a two-state model, we explore the effect of RLC phosphorylation on the kinetics of force development, which proposes that phosphorylation affects the kinetics of both attachment and detachment of cross-bridges. In summary, RLC phosphorylation affects the rate and extent of force redevelopment. These findings were obtained in maximally activated muscle at saturating [Ca(2+) ] and are not explained by changes in the Ca(2+) -sensitivity of acto-myosin interactions. The length-dependence of the rate of force redevelopment, together with the modulation by the state of RLC phosphorylation, suggests that these effects play a role in the Frank-Starling Law of the heart.
Thomas C Irving - 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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structural changes in both the troponin complex and the thick filament may underlie myofilament length dependent activation
Biophysical Journal, 2012Co-Authors: Hsiaoman Hsu, Thomas C Irving, Younss Ait Mou, 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+ at longer sarcomere lengths (SL). The structural basis of this “Length Dependent Activation” (LDA) is not known. 2D X-ray diffraction patterns were obtained using the BioCAT beamline 18ID at the Advanced Photon Source from electrically stimulated (0.2 Hz) intact, twitching papillary muscle isolated from rat hearts during a 10 ms time window in diastole just prior to electrical stimulation. Diffraction patterns were compared from muscles that were stretched to Lmax (SL= ∼2.3 μm) to those taken following a quick release to slack length (SL=∼1.9 μm). We previously reported that myosin heads moved radially inwards at longer SL suggesting that an increased radial extent of crossbridges at longer length cannot explain increased calcium sensitivity so other explanations must be sought. It is known that changes in isoform composition of the troponin complex can markedly affect calcium sensitivity but the role of troponin in the length sensing mechanism underlying LDA is not clear. Here we analyzed the meridional patterns which showed that the 3rd order troponin repeat distance, the 3rd - order troponin reflection intensity and the 2nd order myosin (“forbidden”) meridional reflection all increased significantly (P < 0.01) at Lmax as compared to slack length. Thus, stretching intact heart muscle in diastole induces changes in the structure of both the thick filaments and the thin filaments. It appears, then, that the length sensing mechanism underlying LDA must involve connections of some kind that transmit strain between the thick and thin filament that alter the structure of the troponin complex and, presumably, myofilament contractile properties. Supported by NIH HL075494 and RR08630.
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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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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.
Jolanda Van Der Velden - One of the best experts on this subject based on the ideXlab platform.
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The Frank-Starling Law: a jigsaw of titin proportions.
Biophysical Reviews, 2017Co-Authors: Vasco Sequeira, Jolanda Van Der VeldenAbstract:The Frank–Starling Law dictates that the heart is able to match ejection to the dynamic changes occurring during cardiac filling, hence efficiently regulating isovolumetric contraction and shortening. In the last four decades, efforts have been made to identify a common fundamental basis for the Frank–Starling heart that can explain the direct relationship between muscle lengthening and its increased sensitization to Ca2+. The term ‘myofilament length-dependent activation’ describes the length-dependent properties of the myofilaments, but what is(are) the underlying molecular mechanism(s) is a matter of ongoing debate. Length-dependent activation increases formation of thick-filament strongly-bound cross-bridges on actin and imposes structural–mechanical alterations on the thin-filament with greater than normal bound Ca2+. Stretch-induced effects, rather than changes in filament spacing, appear to be primarily involved in the regulation of length-dependent activation. Here, evidence is provided to support the notion that stretch-mediated effects induced by titin govern alterations of thick-filament force-producing cross-bridges and thin-filament Ca2+-cooperative responses.
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historical perspective on heart function the frank starling Law
Biophysical Reviews, 2015Co-Authors: Vasco Sequeira, Jolanda Van Der VeldenAbstract:More than a century of research on the Frank–Starling Law has significantly advanced our knowledge about the working heart. The Frank–Starling Law mandates that the heart is able to match cardiac ejection to the dynamic changes occurring in ventricular filling and thereby regulates ventricular contraction and ejection. Significant efforts have been attempted to identify a common fundamental basis for the Frank–Starling heart and, although a unifying idea has still to come forth, there is mounting evidence of a direct relationship between length changes in individual constituents (cardiomyocytes) and their sensitivity to Ca2+ ions. As the Frank–Starling Law is a vital event for the healthy heart, it is of utmost importance to understand its mechanical basis in order to optimize and organize therapeutic strategies to rescue the failing human heart. The present review is a historic perspective on cardiac muscle function. We “revive” a century of scientific research on the heart’s fundamental protein constituents (contractile proteins), to their assemblies in the muscle (the sarcomeres), culminating in a thorough overview of the several synergistically events that compose the Frank–Starling mechanism. It is the authors’ personal beliefs that much can be gained by understanding the Frank–Starling relationship at the cellular and whole organ level, so that we can finally, in this century, tackle the pathophysiologic mechanisms underlying heart failure.
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the physiological role of cardiac cytoskeleton and its alterations in heart failure
Biochimica et Biophysica Acta, 2014Co-Authors: Vasco Sequeira, Louise L A M Nijenkamp, Jessica A Regan, Jolanda Van Der VeldenAbstract:Cardiac muscle cells are equipped with specialized biochemical machineries for the rapid generation of force and movement central to the work generated by the heart. During each heart beat cardiac muscle cells perceive and experience changes in length and load, which reflect one of the fundamental principles of physiology known as the Frank-Starling Law of the heart. Cardiac muscle cells are unique mechanical stretch sensors that allow the heart to increase cardiac output, and adjust it to new physiological and pathological situations. In the present review we discuss the mechano-sensory role of the cytoskeletal proteins with respect to their tight interaction with the sarcolemma and extracellular matrix. The role of contractile thick and thin filament proteins, the elastic protein titin, and their anchorage at the Z-disc and M-band, with associated proteins are reviewed in physiologic and pathologic conditions leading to heart failure. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve
Gerrie P Farman - 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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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.
