Mechanical properties of sarcomeres during cardiac myofibrillar relaxation: stretch-induced cross-bridge detachment contributes to early diastolic filling

Stehle, Robert; Solzin, Johannes; Iorga, Bogdan; Gómez, D.; Blaudeck, Natascha; Pfitzer, Gabriele

doi:10.1007/s10974-006-9072-7

Cited by 27 publications

(29 citation statements)

References 37 publications

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“…Nevertheless, this does not seem to significantly slow down the transition of the cardiac myofibril to the relaxed state. The rate constant (k LIN ), the time of the initial slow linear force decay (t LIN ) and the rate constant of the final exponential force decay (k REL ) did not differ among the three genotypes, which is consistent with the notion that a decrease in active force rather than an increase in passive force determines the kinetics of the force decay during relaxation (Stehle et al, 2006).…”

Section: Titin Stiffness Does Not Affect Force-relaxation Kineticssupporting

confidence: 81%

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Elhamine

Radkë

Pfitzer

et al. 2014

Journal of Cell Science

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Cardiac titin is the main determinant of sarcomere stiffness during diastolic relaxation. To explore whether titin stiffness affects the kinetics of cardiac myofibrillar contraction and relaxation, we used subcellular myofibrils from the left ventricles of homozygous and heterozygous N2B-knockout mice which express truncated cardiac titins lacking the unique elastic N2B region. Compared with myofibrils from wild-type mice, myofibrils from knockout and heterozygous mice exhibit increased passive myofibrillar stiffness. To determine the kinetics of Ca 2+ -induced force development (rate constant k ACT ), myofibrils from knockout, heterozygous and wildtype mice were stretched to the same sarcomere length (2.3 mm) and rapidly activated with Ca 2+. Additionally, mechanically induced force-redevelopment kinetics (rate constant k TR ) were determined by slackening and re-stretching myofibrils during Ca 2+ -mediated activation. Myofibrils from knockout mice exhibited significantly higher k ACT , k TR and maximum Ca 2+ -activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca 2+ ] were not significantly different among the three genotypes. These results indicate that increased titin stiffness promotes myocardial contraction by accelerating the formation of force-generating crossbridges without decelerating relaxation.

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Section: Titin Stiffness Does Not Affect Force-relaxation Kineticssupporting

confidence: 81%

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Elhamine

Radkë

Pfitzer

et al. 2014

Journal of Cell Science

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“…Thus, the clustered ''yielding'' is attributable to the cooperativity between adjacent sarcomeres through the structural factors (see the following paragraph). Similar phenomenon was observed during sequential relaxation of cardiac myofibrils, where a stretch can induce sarcomere relaxation only at the wave front of the already relaxing sarcomeres (29). The ''yielding'' sarcomeres may spread over the myofibril under isotonic conditions, where the applied load to each sarcomere is maintained nearly constant irrespective of the occurrence of ''yielding.''…”

Section: Discussionsupporting

confidence: 52%

Inter-sarcomere coordination in muscle revealed through individual sarcomere response to quick stretch

Shimamoto

Suzuki

Mikhailenko

et al. 2009

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

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The force generation and motion of muscle are produced by the collective work of thousands of sarcomeres, the basic structural units of striated muscle. Based on their series connection to form a myofibril, it is expected that sarcomeres are mechanically and/or structurally coupled to each other. However, the behavior of individual sarcomeres and the coupling dynamics between sarcomeres remain elusive, because muscle mechanics has so far been investigated mainly by analyzing the averaged behavior of thousands of sarcomeres in muscle fibers. In this study, we directly measured the length-responses of individual sarcomeres to quick stretch at partial activation, using micromanipulation of skeletal myofibrils under a phase-contrast microscope. The experiments were performed at ADPactivation (1 mM MgATP and 2 mM MgADP in the absence of Ca 2؉ ) and also at Ca 2؉ -activation (1 mM MgATP at pCa 6.3) conditions. We show that under these activation conditions, sarcomeres exhibit 2 distinct types of responses, either ''resisting'' or ''yielding,'' which are clearly distinguished by the lengthening distance of single sarcomeres in response to stretch. These 2 types of sarcomeres tended to coexist within the myofibril, and the sarcomere ''yielding'' occurred in clusters composed of several adjacent sarcomeres. The labeling of Z-line with anti-␣-actinin antibody significantly suppressed the clustered sarcomere ''yielding.'' These results strongly suggest that the contractile system of muscle possesses the mechanism of structure-based inter-sarcomere coordination.myofibril ͉ sarcomere ''yielding'' ͉ Z-line ͉ partial activation T he periodic architecture of striated muscle relies on the series connection of the basic contractile units, called sarcomeres, which are connected through the Z-line to form a myofibril. Each sarcomere is composed of a bipolar array of myofilaments, i.e., the thick (myosin) and thin (actin) filaments. The cyclic interaction of myosin with actin coupled to ATP hydrolysis produces force and motion along the long axis of the myofibril (1, 2). Such characteristics of striated muscle imply that individual sarcomeres are structurally and mechanically interconnected and interact with each other. Tension and length responses of sarcomeres to the external perturbations have revealed various mechanochemical properties of striated muscle, particularly those relating to the mechanism of force generation (3-6) and to the attachment/detachment kinetics of cross-bridges (7-9). On the other hand, the interaction between sarcomeres remains unclear, primarily because the widely used technique for measuring sarcomere response is laser light diffraction, where the individual sarcomere dynamics are obscured by the ensemble averaging of thousands of sarcomeres connected in parallel and in series in muscle fibers.Recent developments in microscopic analysis using skeletal and cardiac myofibrils revealed various dynamic properties of individual sarcomeres (or even half-sarcomeres) upon force generation and relaxation of stria...

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“…However, it remains unclear in which order these events should be reversed during relaxation. The rate constant of the initial, slow myofibrillar force decay (k rel,slow ) following Ca 2ϩ removal suggests that no force-generating cross-bridges become newly formed after Ca 2ϩ removal (26,27,29,30,32,33). This is corroborated by the findings of de Tombe et al (6) that k rel,slow and t rel,slow are insensitive to interventions that decrease the off rate of Tn.…”

mentioning

confidence: 66%

Calcium regulation of troponin and its role in the dynamics of contraction and relaxation

Stehle¹,

Iorga²,

Pfitzer³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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CA 2ϩ SENSITIVITY OF STRIATED muscle contraction is modulated by a number of factors, the mechanism by which force is altered by Ca 2ϩ appears to be complex. If we focus on the level of the regulatory, heterotrimeric troponin complex (Tn ϭ TnC⅐TnI⅐TnT), not only an altered Ca 2ϩ affinity of troponin C (TnC) but also developmental changes in troponin I (TnI) isoforms manifest themselves in altered Ca 2ϩ sensitivity. For example, neonatal hearts, which express the slow skeletal TnI (ssTnI), exhibit an increased Ca 2ϩ sensitivity compared with adult hearts containing the cardiac TnI (cTnI) isoform (19,21,28).In this issue of AJP-Regulatory, Integrative and Comparative Physiology, the article "Myofilament calcium sensitivity does not affect cross-bridge activation-relaxation kinetics" by de Tombe and coworkers (6) investigated whether specific interventions on TnC and TnI leading to Ca 2ϩ sensitization of contraction affect force kinetics in myofibrils. To alter the regulatory function of Tn, they used two straightforward approaches: 1) treatment of the myofibrils with bepridil, a Ca 2ϩ sensitizer known to specifically bind to TnC; and 2) replacement of the endogeneous, fast skeletal Tn (fsTn) in the rabbit psoas myofibril by either cTnC ⅐ cTnI ⅐ cTnT or cTnC⅐ssTnI⅐cTnT. Bepridil and both types of Tn replacements increased the Ca 2ϩ sensitivity (pCa 50 ) of myofibrillar force generation, whereby ssTnI increased it more than cTnI, in agreement with studies on skinned fibers (21,36). Under all conditions, the authors find that Ca 2ϩ activation induces a monoexponential rise of force with a rate constant k act . Yet, importantly, de Tombe et al. (6) found that none of these interventions altered the maximum Ca 2ϩ -activated force nor produced a different k act -force relationship, i.e., for a given active force, the observed kinetics of contraction were similar. Even more intriguingly, neither Tn exchange nor bepridil caused any significant alterations in the kinetics of force decay following rapid Ca 2ϩ removal; no slowing down of mechanical relaxation was observed as one might have expected from the elevated Ca 2ϩ sensitivity induced by these interventions. We learn from these results that the nature of Tn defines the Ca 2ϩ sensitivity of contraction, while it does not influence the kinetics of myofibrillar contraction and relaxation, provided that the complex is able to completely turn off and fully turn on.To better understand the implications of these results, in terms of the kinetic mechanism of Ca 2ϩ -induced contraction, one has to consider why the rate constant of force development is Ca 2ϩ dependent at all. This feature was first approached by Brenner (2) by investigating the Ca 2ϩ dependence of the rate constant of force redevelopment (k tr ) to demonstrate that Ca 2ϩ regulation of force generation results from the gradual increase in the apparent turnover rate constant (f app ) by which crossbridges enter force-generating states. This was inconsistent with the hypothesis that Ca 2ϩ -dependent thin-filament...

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Mechanical properties of sarcomeres during cardiac myofibrillar relaxation: stretch-induced cross-bridge detachment contributes to early diastolic filling

Cited by 27 publications

References 37 publications

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Inter-sarcomere coordination in muscle revealed through individual sarcomere response to quick stretch

Calcium regulation of troponin and its role in the dynamics of contraction and relaxation

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