No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The effects of muscle length on intracellular calcium transients in mammalian cardiac muscle
Abstract
1. The calcium-sensitive photoprotein aequorin was micro-injected into cells of rat and cat ventricular muscles. The resulting light emission is a function of intracellular free calcium concentration ([Ca2+]i). The transient increases in [Ca2+]i that accompany contraction were monitored. 2. After an increase in muscle length, the developed tension increased immediately and then showed a slow increase over a period of minutes. The peak [Ca2+]i in each contraction was initially unchanged after an increase in muscle length but then showed a slow increase with a time course similar to that of the slow tension change. 3. As a consequence of these slow changes, the shape of the tension-length relation depends on the procedure used to determine it and this change in shape can be attributed to changes in activation. 4. Immediately after an increase in muscle length the calcium transient was abbreviated. 5. When a quick release was performed during a contraction, a short-lived increase in the [Ca2+]i was observed following the release. 6. The two previous observations can both be explained if the binding constant of troponin for calcium is a function of developed tension.
... Their "law" describes the heart's most important intrinsic ability in vivo to immediately alter its contractility, and therefore stroke volume, in response to changes in venous return (hence a fundamental principle in cardiovascular physiology). In 1982, Allen and Kurihara published another milestone paper on the detailed cellular basis of the Frank-Starling mechanism, as investigated by analyzing the changes in CaT and tension during twitch in aequorin-microinjected myocardial preparations, accompanied by changes in muscle length [4]. The physiologically most important and most well-known finding in their 1982 work is that following a sudden change in muscle length, of either shortening or lengthening (by as much as 20%), twitch force is markedly, instantly changed (decreased and increased when shortened and lengthened, respectively) but the peak aequorin light signal barely changes, indicating that the Frank-Starling mechanism is primarily regulated at the myofibrillar level (Fig. 4). ...
... As documented by Kentish et al. [37] using skinned rat right ventricular trabeculae, myofibrillar Ca 2+ sensitivity is increased in response to an increase in sarcomere length by an order of 0.1 μm. Therefore, the findings by Allen and Kurihara [4] indicate a feedback mechanism between Ca 2+ -binding to TnC and muscle length; viz., when intact muscle length is shortened, Ca 2+ is dissociated from TnC and therefore released in the myoplasm coupled with a decrease in the affinity of TnC for Ca 2+ . ...
... The Anrep effect was first described in 1912 by Gleb von Anrep [72], a Russia-born Egyptian physiologist; this effect constitutes a mechanism by which the heart gradually adapts to an increase in afterload, which occurs after the Frank-Starling effect. It should be addressed that by measuring CaT and tension over a long period of time (~ 30 min), Allen and Kurihara [4] first shed light on the cellular basis of the Anrep effect at the muscle tissue level; they showed that after an increase in muscle length, tension increases dramatically and then shows a slow increase over a period of minutes. It is important that CaT is unchanged immediately after an increase in muscle length; however, it then shows a slow increase with a time course similar to that of the slow tension change. ...
Of the ions involved in myocardial function, Ca ²⁺ is the most important. Ca ²⁺ is crucial to the process that allows myocardium to repeatedly contract and relax in a well-organized fashion; it is the process called excitation–contraction coupling. In order, therefore, for accurate comprehension of the physiology of the heart, it is fundamentally important to understand the detailed mechanism by which the intracellular Ca ²⁺ concentration is regulated to elicit excitation–contraction coupling. Aequorin was discovered by Shimomura, Johnson and Saiga in 1962. By taking advantage of the fact that aequorin emits blue light when it binds to Ca ²⁺ within the physiologically relevant concentration range, in the 1970s and 1980s, physiologists microinjected it into myocardial preparations. By doing so, they proved that Ca ²⁺ transients occur upon membrane depolarization, and tension development (i.e., actomyosin interaction) subsequently follows, dramatically advancing the research on cardiac excitation–contraction coupling.
... Any shift in the delicate balance in Ca 2+ handling will cause a net change in cellular Ca 2+ and influence EC coupling. Indeed, mechanisms that modulate EC coupling contribute to the repertoire of adaptive behaviour that exist in cardiac tissue (Frank, 1895;Patterson and Starling, 1914;Allen and Kurihara, 1982). ...
... Despite having been described for over a century, the mechanistic basis of how cardiomyocytes sense changes in load and transduce these to modulate contractile force is not fully understood. It is known that stretch-induced increase in force production is biphasic: an abrupt increase in force coincides with stretch, which is then followed by a slower response developing over a period of seconds to minutes (the slow force response or SFR) also known as the Anrep effect (Parmley and Chuck, 1973;Allen and Kurihara, 1982;Tucci et al., 1984;White et al., 1995). In comparison to the mechanism underpinning the rapid response-which is relatively well described (Allen and Blinks, 1978;Konhilas et al., 2002;Shiels and White, 2008;Sequeira and van der Velden, 2015)-the SFR mechanism is not well characterized. ...
... In comparison to the mechanism underpinning the rapid response-which is relatively well described (Allen and Blinks, 1978;Konhilas et al., 2002;Shiels and White, 2008;Sequeira and van der Velden, 2015)-the SFR mechanism is not well characterized. It is known that SFR is correlated with an increase in magnitude of the systolic Ca 2+ transient (Allen and Kurihara, 1982;Allen et al., 1988;Le Guennec et al., 1991), and mechanically-activated ion channels have been invoked as part of the mechanism (Gannier et al., 1994;Calaghan and White, 2004;Ward et al., 2008). ...
Throughout its lifetime the heart is buffeted continuously by dynamic mechanical forces resulting from contraction of the heart muscle itself and fluctuations in haemodynamic load and pressure. These forces are in flux on a beat-by-beat basis, resulting from changes in posture, physical activity or emotional state, and over longer timescales due to altered physiology (e.g. pregnancy) or as a consequence of ageing or disease (e.g. hypertension). It has been known for over a century of the heart’s ability to sense differences in haemodynamic load and adjust contractile force accordingly (Frank, Z. biology, 1895, 32, 370–447; Anrep, J. Physiol., 1912, 45 (5), 307–317; Patterson and Starling, J. Physiol., 1914, 48 (5), 357–79; Starling, The law of the heart (Linacre Lecture, given at Cambridge, 1915), 1918). These adaptive behaviours are important for cardiovascular homeostasis, but the mechanism(s) underpinning them are incompletely understood. Here we present evidence that the mechanically-activated ion channel, Piezo, is an important component of the Drosophila heart’s ability to adapt to mechanical force. We find Piezo is a sarcoplasmic reticulum (SR)-resident channel and is part of a mechanism that regulates Ca2+ handling in cardiomyocytes in response to mechanical stress. Our data support a simple model in which Drosophila Piezo transduces mechanical force such as stretch into a Ca2+ signal, originating from the SR, that modulates cardiomyocyte contraction. We show that Piezo mutant hearts fail to buffer mechanical stress, have altered Ca2+ handling, become prone to arrhythmias and undergo pathological remodelling.
... Footwears such as the thickness of the midsole and heel-toe drop (HTD) have been considered in studies of young athletes that could influence a runner's performance, particularly in cushioning (Hasegawa et al., 2007;Sinclair et al., 2012;Chambon et al., 2015;Nigg et al., 2015). Increasing the midsole thickness could protonate the runner's effective leg length, such as the Nike Vaporfly 4%, which has a 31-mm heel height (Allen and Kurihara, 1982). It could decrease energy loss for the runner by increasing an effective leg length of 8 mm (Pontzer, 2007;Hoogkamer et al., 2018). ...
... It was worth noting that a 16-mm shoe drop in this study did not cause significant changes in joints' (knee and ankle) torque, which would be associated with the midsole's three layers to modify the stress around the joints (ankle and knee). In addition, the effective limb length of the leg as a strut drives the scaling of locomotor cost for a runner, which was the leg length with the HTD when running with shoes (Allen and Kurihara, 1982). The HTD of the IRS was 9.5 mm more than that of NRS which could protonate the runner's effective leg length, in other words, increased the force arm of the knee joint, offsetting the influence of the ground reaction force, which might be the reason why no significant difference was found in the knee joint moment (Allen and Kurihara, 1982;Pontzer, 2007;Hoogkamer et al., 2018). ...
... In addition, the effective limb length of the leg as a strut drives the scaling of locomotor cost for a runner, which was the leg length with the HTD when running with shoes (Allen and Kurihara, 1982). The HTD of the IRS was 9.5 mm more than that of NRS which could protonate the runner's effective leg length, in other words, increased the force arm of the knee joint, offsetting the influence of the ground reaction force, which might be the reason why no significant difference was found in the knee joint moment (Allen and Kurihara, 1982;Pontzer, 2007;Hoogkamer et al., 2018). This study suggested that it was essential to combine the HTD and hardness of the midsole into account when designing a shoe to improve cushioning and reduce the risk of injuries. ...
The study aimed to research the effects of innovative running shoes (a high heel-to-toe drop and special structure of midsole) on the biomechanics of the lower limbs and perceptual sensitivity in female runners. Fifteen healthy female runners were recruited to run through a 145-m runway with planted force plates at one peculiar speed (3.6 m/s ± 5%) with two kinds of shoe conditions (innovative running shoes vs. normal running shoes) while getting biomechanical data. The perception of shoe characteristics was assessed simultaneously through a 15-cm visual analog scale. The statistical parametric mapping technique calculated the time-series parameters. Regarding 0D parameters, the ankle dorsiflexion angle of innovative running shoes at touchdown was higher, and the peak dorsiflexion angle, range of motion, peak dorsiflexion velocity, and plantarflexion moment on the metatarsophalangeal joint of innovative running shoes during running were significantly smaller than those of normal running shoes (all p < 0.001). In addition, the braking phase and the time of peak vertical force 1 of innovative running shoes were found to be longer than those of normal running shoes (both p < 0.05). Meanwhile, the average vertical loading rate 1, peak vertical loading rate 1, peak braking force, and peak vertical force 1 in the innovative running shoes were lower than those of the normal running shoes during running (both p < 0.01). The statistical parametric mapping analysis exhibited a higher ankle dorsiflexion angle (0–4%, p < 0.05), a smaller knee internal rotation angle (0–6%, p < 0.05) (63–72%, p < 0.05), a decreased vertical ground reaction force (11–17%, p = 0.009), and braking anteroposterior ground reaction force (22–27%, p = 0.043) for innovative running shoes than normal running shoes. Runners were able to perceive the cushioning of innovative running shoes was better than that of normal running shoes. These findings suggested combining the high offset and structure of the midsole would benefit the industrial utilization of shoe producers in light of reducing the risk of running injuries for female runners.
... He recognized that this relationship was so important that he called it the "law of the heart". Implicit in this law is that the force of contraction is a single-valued function of the muscle length as shown in Figure 1 adapted from Allen and Kurihara's experiment on trabeculae [2]. Starling's law of the heart is a foundation stone of cardiac physiology and it underpins our understanding of heart function in both normal and diseased states [3]. ...
... The adaptive force ∆F (green double-headed arrow) is the force needed to account for the Anrep effect. F-S curve redrawn from Allen and Kurihara [2]. ...
... Proof of Theorem A1. By the assumption of the theorem C k+1 = φ k+1 > φ k = C k and this implies that k+1 > k from (2). Therefore, ...
The heart has two intrinsic mechanisms to enhance contractile strength that compensate for increased mechanical load to help maintain cardiac output. When vascular resistance increases the ventricular chamber initially expands causing an immediate length-dependent increase of contraction force via the Frank-Starling mechanism. Additionally, the stress-dependent Anrep effect slowly increases contraction force that results in the recovery of the chamber volume towards its initial state. The Anrep effect poses a paradox: how can the cardiomyocyte maintain higher contractility even after the cell length has recovered its initial length? Here we propose a surface mechanosensor model that enables the cardiomyocyte to sense different mechanical stresses at the same mechanical strain. The cell-surface mechanosensor is coupled to a mechano-chemo-transduction feedback mechanism involving three elements: surface mechanosensor strain, intracellular Ca2+ transient, and cell strain. We show that in this simple yet general system, contractility autoregulation naturally emerges, enabling the cardiomyocyte to maintain contraction amplitude despite changes in a range of afterloads. These nontrivial model predictions have been experimentally confirmed. Hence, this model provides a new conceptual framework for understanding the contractility autoregulation in cardiomyocytes, which contributes to the heart’s intrinsic adaptivity to mechanical load changes in health and diseases.
... The duration of our simulated Ca 2+ transients increased with decreasing sarcomere length and decreasing afterload for isometric and work-loop contractions, respectively (Figure 4). The prolongation of the Ca 2+ transient associated with isometric contractions at shorter muscle lengths is consistent with experimental studies on isolated rat cardiac tissues (Allen and Kurihara, 1982;Kentish and Wrzosek, 1998). At shorter muscle lengths, the affinity of Ca 2+ for troponin-C is lower, hence less Ca 2+ is bound to troponin-C, resulting in a wider Ca 2+ transient. ...
... Despite a prolongation of the Ca 2+ transient due to either a reduction of initial muscle length in isometric contractions or a reduction of afterload in work-loop contractions, the peaks of the simulated Ca 2+ transients remained relatively constant for both modes of contraction. Studies on rat cardiac trabeculae have reported no change in the peak Ca 2+ transient in isometric contractions at different muscle lengths (Allen and Kurihara, 1982;Backx and Ter Keurs, 1993;Kentish and Wrzosek, 1998). Studies on the effect of a shortening contraction on the peak of the Ca 2+ transient are not so clear. ...
... In our simulations, the peak of the Ca 2+ transient remained relatively constant, because only a fraction of peak force development had occurred at the time of peak Ca 2+ (Figure 5). The completion of force development occurs after the peak Ca 2+ has passed and is reflected in the prolongation of the declining phase of the Ca 2+ transient (Allen and Kurihara, 1982). ...
In experimental studies on cardiac tissue, the end-systolic force-length relation (ESFLR) has been shown to depend on the mode of contraction: isometric or isotonic. The isometric ESFLR is derived from isometric contractions spanning a range of muscle lengths while the isotonic ESFLR is derived from shortening contractions across a range of afterloads. The ESFLR of isotonic contractions consistently lies below its isometric counterpart. Despite the passing of over a hundred years since the first insight by Otto Frank, the mechanism(s) underlying this protocol-dependent difference in the ESFLR remain incompletely explained. Here, we investigate the role of mechano-calcium feedback in accounting for the difference between these two ESFLRs. Previous studies have compared the dynamics of isotonic contractions to those of a single isometric contraction at a length that produces maximum force, without considering isometric contractions at shorter muscle lengths. We used a mathematical model of cardiac excitation-contraction to simulate isometric and force-length work-loop contractions (the latter being the 1D equivalent of the whole-heart pressure-volume loop), and compared Ca²⁺ transients produced under equivalent force conditions. We found that the duration of the simulated Ca²⁺ transient increases with decreasing sarcomere length for isometric contractions, and increases with decreasing afterload for work-loop contractions. At any given force, the Ca²⁺ transient for an isometric contraction is wider than that during a work-loop contraction. By driving simulated work-loops with wider Ca²⁺ transients generated from isometric contractions, we show that the duration of muscle shortening was prolonged, thereby shifting the work-loop ESFLR toward the isometric ESFLR. These observations are explained by an increase in the rate of binding of Ca²⁺ to troponin-C with increasing force. However, the leftward shift of the work-loop ESFLR does not superimpose on the isometric ESFLR, leading us to conclude that while mechano-calcium feedback does indeed contribute to the difference between the two ESFLRs, it does not completely account for it.
... The relationship between increasing contraction force and increasing muscle length stands as one of the great foundation stones of cardiac physiology. This fundamental relationship at the sarcomeric level is shown by the monotonically increasing F-S curve (F-S) in Fig. 6B, based on experiments using trabeculae (Allen & Kurihara, 1982), which shows developed force (F) as a function of sarcomere length (L). ...
... F (green arrow) is the force SSC needs to generate. F-S curve redrawn from Allen & Kurihara (1982). C and D, time evolution of left ventricular (LV) haemodynamic parameters following transaortic constriction (TAC). ...
... Anrep's observation was the first indication that the heart responded not only to mechanical strain as described by Starling's law but also to mechanical stress. The response of the heart to an increase in the outflow resistance shown in Fig. 6 actually has four names: (1) the Anrep effect, which honors its discoverer; (2) homeometric autoregulation (Sarnoff et al. 1960), which emphasizes the increase of contractility at the same muscle length; (3) slow force response (Parmley & Chuck, 1973;Donald et al. 1976;Allen & Kurihara, 1982;Kentish & Wrzosek, 1998), which emphasizes the slow time-dependent signalling (up to tens of minutes) to increase inotropy; and (4) stress-stimulated contractility (Seo et al. 2014), which highlights the role of stress instead of strain in increasing contraction force. We think that the attachment of four different names to the same phenomenon attests to the long history of trying to understand this puzzling phenomenon. ...
Cardiac excitation‐contraction (E‐C) coupling is influenced by (at least) three dynamic systems that couple and feedback to one another (see Abstract Figure). Here we review the mechanical effects on cardiomyocytes that include mechano‐electro‐transduction (commonly referred to as mechano‐electric coupling, MEC) and mechano‐chemo‐transduction (MCT) mechanisms at cell and molecular levels which couple to Ca²⁺‐electro and E‐C coupling reviewed elsewhere. These feedback loops from muscle contraction and mechano‐transduction to the Ca²⁺ homeodynamics and to the electrical excitation are essential for understanding the E‐C coupling dynamic system and arrhythmogenesis in mechanically loaded hearts. This white paper comprises two parts, each reflecting key aspects from the 2018 UC Davis symposium: MEC (how mechanical load influences electrical dynamics) and MCT (how mechanical load alters cell signalling and Ca²⁺ dynamics). Of course, such separation is artificial since Ca²⁺ dynamics profoundly affect ion channels and electrogenic transporters and vice versa. In time, these dynamic systems and their interactions must become fully integrated, and that should be a goal for a comprehensive understanding of how mechanical load influences cell signalling, Ca²⁺ homeodynamics and electrical dynamics. In this white paper we emphasize current understanding, consensus, controversies and the pressing issues for future investigations. Space constraints make it impossible to cover all relevant articles in the field, so we will focus on the topics discussed at the symposium. image
... The Slow Force Response (SFR) is an import ant regulatory mechanism of adaptation of myo cardial contractility to sudden increase in the external mechanical load which is accompanied by the stretch of myocardial fibers [1,2]. This slow response is following by the rapid stretch induced increase in contractility, which is known as the Frank-Starling Mechanism (FSM), lasts at least several minutes, and it has been shown on the lev els of single cell [3][4][5], isolated muscle [6][7][8][9][10] and in the intact ventricle [11][12][13]. The slow changes during SFR may exceed 30% of the amplitude of contraction developed immediately after stretch, making its expression to be highly important in the mechanical regulation of cardiac function. ...
... The phenomenology of the SFR is not fully elu cidated [1,2]. Early evidence showed that the SFR is accompanied by elevation of the peak cytosolic Ca 2+ ; therefore, it has been proposed that the elevation of intracellular Ca 2+ is a prereq uisite for the development of SFR [6]. Further advances revealed that the following mechanisms and pathways participate in the Ca 2+ accumula tion and generation of SFR: (1) stretch activated non selective cation channels of the sarcoplasmic membrane [14], (2) Na + /H + and Na + /Ca 2+ exchangers and Na + /K + pump [15][16][17], (3) cyclic AMP [12,18], (4) angiotensin II and endo thelin related mechanisms [5,10,15,19,20], (5) activation of some kinases like CaMKII or p38 MAPK [1,[21][22][23], (6) mediation of nitric oxide and reactive oxygen species systems [24,25], and (7) mineralocorticoids [26] which are involved into activation of Na + /H + exchanger and there fore affect the mechanism(s) of the SFR. ...
The Slow Force Response (SFR) is an important mechanism of adaptation of myocardial contractility to the mechanical load. The discrepancies between the SFR in atrial and ventricular myocardium are poorly characterized; moreover, the correlation between the mechanical response and underlying changes in Ca2+ transient are unknown. We measured simultaneous slow changes in force and Ca2+ transient developed in right atrial and ventricular (RA and RV) muscles of healthy control rats (CONT) and rats with monocrotaline-induced pulmonary heart failure (MCT) as a response to rapid muscle stretch. The SFR was positive in RA muscles but negative in RV muscles in CONT and MCT groups. The extent of SFR was significantly higher in the failing myocardium. The slow changes in peak active force showed little correlation with rate- and time-related characteristics of isometric force. The relative changes in Ca2+ transient diastolic level, amplitude, time-to-peak and time to decay from peak to 50% amplitude at the end of SFR were significantly smaller compared to the extent of SFR. Plotting the extent of SFR as peak active force vs the extent of change in Ca2+ transient diastolic level or amplitude revealed that only the latter followed nearly linear behavior while the former had no substantial correlation. We conclude that the minor changes in Ca2+ transient characteristics during SFR underlie the much greater changes observed in the peak active force. The atrioventricular discrepancies in the SFR indicate different adaptive responses of the contractility of these chambers to the external mechanical loading.
... First, the preload was more influential on the overall duration of the Ca 2 þ transient than afterload, as t 90 and t dur10 (Ca 2 þ ) were shorter at the lower preload while being afterload independent (Fig. 5I). On initial inspection, the preload dependency of the Ca 2 þ transient duration measured within this study directly contradicts preexisting observations that greater muscle lengths are associated with shorter Ca 2 þ transients (48,49) and with those reporting no length dependence (13). However, the observed behavior seems to align with a force-based binding affinity of TnC (50,51). ...
... The time to peak Ca 2 þ was also independent of preload and afterload (Fig. 5E). In the literature, the time to peak Ca 2 þ is length independent in healthy cardiac muscle (13,47,48), and the afterload independence is also consistent with data collected from small-to medium-sized mammalian heart tissues (3,4,8). We found that the integral of the Ca 2 þ transient (CTI), which provides an insight into the exposure of internal structures to Ca 2 þ , was independent of afterload and preload (Fig. 4A). ...
Preload and afterload dictate the dynamics of the cyclical work-loop contraction that the heart undergoes in vivo. Cellular Ca ²⁺ dynamics drive contraction, but the effects of afterload alone on the Ca ²⁺ transient are inconclusive. No study has investigated whether the putative afterload dependence of the Ca ²⁺ transient is preload dependent. This study is designed to provide the first insight into the Ca ²⁺ handling of cardiac trabeculae undergoing work-loop contractions, with the aim to examine whether the conflicting afterload dependency of the Ca ²⁺ transient can be accounted for by considering preload under isometric and physiological work‑loop contractions. Thus, we subjected ex vivo rat right-ventricular trabeculae, loaded with the fluorescent dye Fura‑2, to work‑loop contractions over a wide range of afterloads at two preloads while measuring stress, length changes, and Ca ²⁺ transients. Work‑loop control was implemented with a real-time Windkessel model to mimic the contraction patterns of the heart in vivo. We extracted a range of metrics from the measured steady‑state twitch stress and Ca ²⁺ transients, including the amplitudes, time courses, rates of rise, and integrals. Results show that parameters of stress were afterload and preload dependent. In contrast, the parameters associated with Ca ²⁺ transients displayed a mixed dependence on afterload and preload. Most notably, its time course was afterload-dependent - an effect augmented at the greater preload. This study reveals that the afterload dependence of cardiac Ca ²⁺ transients is modulated by preload, which brings the study of Ca ²⁺ transients during isometric contractions into question when aiming to understand physiological Ca ²⁺ handling.
... In view of these findings, Sun et al. (2009) concluded a minimal role for cycling crossbridges in thin filament activation. One related set of much earlier experiments that requires interpretation are studies showing that upon a quick transient release of cardiac muscle in a twitch contraction, there is a transient rise "bump" in the cellular Ca 2+ transient as measured with the aequorin technique (Allen and Kurihara, 1982). Sun et al. (2009) indicated that this is due to a small component of tension on cTnC Ca 2+ affinity that is not a major regulator of thin filament activation. ...
... With deactivation of the thin filaments, tension and pressure fall, but the rate of detachment of the ensemble of myosins lags the Ca 2+ -reuptake kinetics, leading to residually active regulatory units in thin filaments. A is adapted with permission from RadioGraphics (Sheth et al., 2015), with the addition of the sarcomere length (Aguirre et al., 2014) and the Ca 2+ pulse (Allen and Kurihara, 1982) time series. See text for further discussion. ...
Our review focuses on sarcomere regulatory mechanisms with a discussion of cardiac-specific modifications to the three-state model of thin filament activation from a blocked to closed to open state. We discuss modulation of these thin filament transitions by Ca2+, by crossbridge interactions, and by thick filament–associated proteins, cardiac myosin–binding protein C (cMyBP-C), cardiac regulatory light chain (cRLC), and titin. Emerging evidence supports the idea that the cooperative activation of the thin filaments despite a single Ca2+ triggering regulatory site on troponin C (cTnC) cannot be considered in isolation of other functional domains of the sarcomere. We discuss long- and short-range interactions among these domains with the regulatory units of thin filaments, including proteins at the barbed end at the Z-disc and the pointed end near the M-band. Important to these discussions is the ever-increasing understanding of the role of cMyBP-C, cRLC, and titin filaments. Detailed knowledge of these control processes is critical to the understanding of mechanisms sustaining physiological cardiac state with varying hemodynamic load, to better defining genetic and acquired cardiac disorders, and to developing targets for therapies at the level of the sarcomeres.
... The stretch response is commonly referred to as the Frank-Starling relationship (Frank 1895;Patterson and Starling 1914). At least 3 different cellular mechanisms are involved in the Frank-Starling relationship (for review see (Allen and Kentish 1985)): (i) increased overlap between contractile protein myofilaments (Fabiato and Fabiato 1975;Gordon et al. 1966); (ii) increased Ca 2+ sensitivity of the contractile proteins (Fukuda and Granzier 2005;Hibberd and Jewell 1982); and (iii) increased Ca 2+ transients (the systolic rise in intracellular Ca 2+ ([Ca 2+ ] i ) which activates the contractile proteins) which gradually become larger over some minutes after a stretch (Allen and Kurihara 1982;Kentish and Wrzosek 1998;Ward et al. 2008). This review will focus on the third of these cellular mechanisms since there is still debate about this aspect of cardiac regulation. ...
... They argued that the slow phenomenon was likely to be caused by changes in the degree of activation of the contractile proteins. It was later shown that the SFR was accompanied by a slow increase in the magnitude of the Ca 2+ transients which continued for several minutes (Allen and Kurihara 1982;Kentish and Wrzosek 1998;Ward et al. 2008). Figure 1 shows a representative SFR from a rat ventricular trabecula. ...
The mechanical response of the heart to myocardial stretch has been understood since the work of muscle physiologists more than 100 years ago, whereby an increase in ventricular chamber filling during diastole increases the subsequent force of contraction. The stretch-induced increase in contraction is biphasic. There is an abrupt increase in the force that coincides with the stretch (the rapid response), which is then followed by a slower response that develops over several minutes (the slow force response, or SFR). The SFR is associated with a progressive increase in the magnitude of the Ca²⁺ transient, the event that initiates myocyte cross-bridge cycling and force development. However, the mechanisms underlying the stretch-dependent increase in the Ca²⁺ transient are still debated. This review outlines recent literature on the SFR and summarizes the different stretch-activated Ca²⁺ entry pathways. The SFR might result from a combination of several different cellular mechanisms initiated in response to activation of different cellular stretch sensors.
... Therefore, a structurally and physiologically based understanding of the influence of non-XB structures on cardiac muscle force is pending. The force response upon myocardial muscle stretching, which occurs during cardiac filling, is characterized by two distinct phenomena: by an instantaneous increase in twitch force, the so-called Frank -Starling mechanism [37] and by a several minute lasting slow increase in twitch, the so-called slow force response [38]. There is extensive evidence that titin stress -length dependency, as the stress is normalized to maximum isometric stress (P/P 0 ). ...
... Notably, with the onset of stimulation at t ¼ 0 s, the intact trabecula contracted maximally and produced about 3% active muscle stress (P/P 0 ) at 0.75 L 0 (dark blue line; table 1). This is in agreement with other studies reporting almost no active muscle force at 0.7 L 0 -0.75 L 0 [4,38,57,59]. There is no RFE in intact cardiac trabecula following active stretching under control conditions (dark blue solid line; no XB inhibition (without blebbistatin)) nor under blebbistatin conditions (light blue solid line; with XB inhibition). ...
Force enhancement (FE) is a phenomenon that is present in skeletal muscle. It is characterized by progressive forces upon active stretching-distinguished by a linear rise in force-and enhanced isometric force following stretching (residual FE (RFE)). In skeletal muscle, non-cross-bridge (XB) structures may account for this behaviour. So far, it is unknown whether differences between non-XB structures within the heart and skeletal muscle result in deviating contractile behaviour during and after eccentric contractions. Thus, we investigated the force response of intact cardiac trabeculae during and after isokinetic eccentric muscle contractions (10% of maximum shortening velocity) with extensive magnitudes of stretch (25% of optimum muscle length). The different contributions of XB and non-XB structures to the total muscle force were revealed by using an actomyosin inhibitor. For cardiac trabeculae, we found that the force-length dynamics during long stretch were similar to the total isometric force-length relation. This indicates that no (R)FE is present in cardiac muscle while stretching the muscle from 0.75 to 1.0 optimum muscle length. This finding is in contrast with the results obtained for skeletal muscle, in which (R)FE is present. Our data support the hypothesis that titin stiffness does not increase with activation in cardiac muscle.
... While the conditions in the current study differ from traditional studies of myofilament kinetics in permeabilized tissues where the calcium concentration is fixed [6,9,14,15,17,20], the substantial strain-rate dependence of the peak stress-response and half-time of force decay from the peak to the minimum stress-response are likely independent of any strain-dependent changes in calcium handling. Length changes of a muscle modify the calcium transient detected over several beats, but such changes take minutes to develop [23][24][25]. Because this study assesses the stress-response within the same twitch, such long-term changes in calcium flux would not affect the data reported here. ...
Mechanical Control of Relaxation refers to the dependence of myocardial relaxation on the strain rate just prior to relaxation, but the mechanisms of enhanced relaxation are not well characterized. This study aimed to characterize how crossbridge kinetics varied with strain rate and time-to-stretch as the myocardium relaxed in early diastole. Ramp-stretches of varying rates (amplitude = 1% muscle length) were applied to intact rat cardiac trabeculae following a load-clamp at 50% of the maximal developed twitch force, which provides a first-order estimate of ejection and coupling to an afterload. The resultant stress-response was calculated as the difference between the time-dependent stress profile between load-clamped twitches with and without a ramp-stretch. The stress-response exhibited features of the step-stretch response of activated, permeabilized myocardium, such as distortion-dependent peak stress, rapid force decay related to crossbridge detachment, and stress recovery related to crossbridge recruitment. The peak stress was strain rate dependent, but the minimum stress and the time-to-minimum stress values were not. The initial rapid change in the stress-response indicates enhanced crossbridge detachment at higher strain rates during relaxation in intact cardiac trabeculae. Physiologic considerations, such as time-varying calcium, are discussed as potential limitations to fitting these data with traditional distortion-recruitment models of crossbridge activity.
... Changes in the Na + /Ca 2+ exchanger, whose current is responsible for the increased CaTs [57,58] and the increased affinity of TnC for calcium ions [59], are considered to be the mechanism of modulation of the AP shape under the influence of stretching, which is consistent with our results. ...
There are only a few studies devoted to the comparative and simultaneous study of the mechanisms of the length-dependent regulation of atrial and ventricular contractility. Therefore, an isometric force-length protocol was applied to isolated guinea pig right atrial (RA) strips and ventricular (RV) trabeculae, with a simultaneous measurement of force (Frank–Starling mechanism) and Ca2+ transients (CaT) or transmembrane action potentials (AP). Over the entire length-range studied, the duration of isometric contraction, CaT and AP, were shorter in the RA myocardium than in the RV myocardium. The RA myocardium was stiffer than the RV myocardium. With the increasing length of the RA and RV myocardium, the amplitude and duration of isometric contraction and CaT increased, as well as the amplitude and area of the “CaT difference curves” (shown for the first time). However, the rates of the tension development and relaxation decreased. No contribution of AP duration to the heterometric regulation of isometric tension was found in either the RA or RV myocardium of the guinea pig. Changes in the degree of overlap of the contractile proteins of the guinea pig RA and RV myocardium mainly affect CaT kinetics but not AP duration.
... We constrained the ToR-ORd-Land model so that it provided physiological calcium transients based on the literature [47,48] (S2 File), and where peak, rest and duration of the isometric tension transient were within ranges of measured values in mammals [49,50] and allowed the simulations to achieve LV pressure peak and duration that were consistent with clinical data. Similarly, the calcium transient simulated with the Courtemanche model was constrained to be consistent with the literature [47,48,51] (S3 File), while the isometric active tension was bound to be physiological [9,50,[52][53][54][55][56][57][58][59]. We finally applied HM on the electrophysiology Eikonal model alone to achieve physiological total activation times of the atria and the ventricles, as the simulated activation times are independent of the mechanics simulation (S4 File). ...
Cardiac pump function arises from a series of highly orchestrated events across multiple scales. Computational electromechanics can encode these events in physics-constrained models. However, the large number of parameters in these models has made the systematic study of the link between cellular, tissue, and organ scale parameters to whole heart physiology challenging. A patient-specific anatomical heart model, or digital twin, was created. Cellular ionic dynamics and contraction were simulated with the Courtemanche-Land and the ToR-ORd-Land models for the atria and the ventricles, respectively. Whole heart contraction was coupled with the circulatory system, simulated with CircAdapt, while accounting for the effect of the pericardium on cardiac motion. The four-chamber electromechanics framework resulted in 117 parameters of interest. The model was broken into five hierarchical sub-models: tissue electrophysiology, ToR-ORd-Land model, Courtemanche-Land model, passive mechanics and CircAdapt. For each sub-model, we trained Gaussian processes emulators (GPEs) that were then used to perform a global sensitivity analysis (GSA) to retain parameters explaining 90% of the total sensitivity for subsequent analysis. We identified 45 out of 117 parameters that were important for whole heart function. We performed a GSA over these 45 parameters and identified the systemic and pulmonary peripheral resistance as being critical parameters for a wide range of volumetric and hemodynamic cardiac indexes across all four chambers. We have shown that GPEs provide a robust method for mapping between cellular properties and clinical measurements. This could be applied to identify parameters that can be calibrated in patient-specific models or digital twins, and to link cellular function to clinical indexes.
... Studies on the mechanisms of Frank-Starling response of cardiac muscles have been concentrated on the lengthdependency of myofilament Ca 2+ sensitivity (Allen and Kurihara, 1982;Shiels et al., 2006;Shiels and White, 2008;de Tombe et al., 2010). Our finding that cTnI-ND,Tnni3 −/− enhances Frank-Starling response to preload without increasing LVEDV or resting SL opens a new dimension for mechanistic investigations. ...
Cardiac troponin I (cTnI) of higher vertebrates has evolved with an N-terminal extension, of which deletion via restrictive proteolysis occurs as a compensatory adaptation in chronic heart failure to increase ventricular relaxation and stroke volume. Here, we demonstrate in a transgenic mouse model expressing solely N-terminal truncated cTnI (cTnI-ND) in the heart with deletion of the endogenous cTnI gene. Functional studies using ex vivo working hearts showed an extended Frank-Starling response to preload with reduced left ventricular end diastolic pressure. The enhanced Frank-Starling response effectively increases systolic ventricular pressure development and stroke volume. A novel finding is that cTnI-ND increases left ventricular relaxation velocity and stroke volume without increasing the end diastolic volume. Consistently, the optimal resting sarcomere length (SL) for maximum force development in cTnI-ND cardiac muscle was not different from wild-type (WT) control. Despite the removal of the protein kinase A (PKA) phosphorylation sites in cTnI, β-adrenergic stimulation remains effective on augmenting the enhanced Frank-Starling response of cTnI-ND hearts. Force–pCa relationship studies using skinned preparations found that while cTnI-ND cardiac muscle shows a resting SL–resting tension relationship similar to WT control, cTnI-ND significantly increases myofibril Ca²⁺ sensitivity to resting tension. The results demonstrate that restrictive N-terminal deletion of cTnI enhances Frank-Starling response by increasing myofilament sensitivity to resting tension rather than directly depending on SL. This novel function of cTnI regulation suggests a myofilament approach to utilizing Frank-Starling mechanism for the treatment of heart failure, especially diastolic failure where ventricular filling is limited.
... (Allen and Kentish, 1985;Farman et al., 2010;Campbell, 2011;Sagawa et al., 1988;de Tombe et al., 2010). Length-dependent changes in calcium handling contribute to the response (Fabiato and Fabiato, 1975;Parmley and Chuck, 1973;Vahl et al., 1998;Allen and Kurihara, 1982;Kentish et al., 1986), but the primary mechanisms driving the Frank-Starling relationship probably stem from the myofilaments (i.e., the thick filaments of myosin and thin filaments of actin that are responsible for myocardial force production; Farman et al., 2010;Hibberd and Jewell, 1982;Smith et al., 2009;Cazorla et al., 2001;McDonald and Moss, 1995;Milani-Nejad et al., 2015;Hanft and McDonald, 2010). As chemically permeabilized cardiac cells are stretched, they become more sensitive to Ca 2+ and develop more force. ...
In healthy hearts, myofilaments become more sensitive to Ca2+ as the myocardium is stretched. This effect is known as length-dependent activation and is an important cellular-level component of the Frank–Starling mechanism. Few studies have measured length-dependent activation in the myocardium from failing human hearts. We investigated whether ischemic and non-ischemic heart failure results in different length-dependent activation responses at physiological temperature (37°C). Myocardial strips from the left ventricular free wall were chemically permeabilized and Ca2+-activated at sarcomere lengths (SLs) of 1.9 and 2.3 µm. Data were acquired from 12 hearts that were explanted from patients receiving cardiac transplants; 6 had ischemic heart failure and 6 had non-ischemic heart failure. Another 6 hearts were obtained from organ donors. Maximal Ca2+-activated force increased at longer SL for all groups. Ca2+ sensitivity increased with SL in samples from donors (P < 0.001) and patients with ischemic heart failure (P = 0.003) but did not change with SL in samples from patients with non-ischemic heart failure. Compared with donors, troponin I phosphorylation decreased in ischemic samples and even more so in non-ischemic samples; cardiac myosin binding protein-C (cMyBP-C) phosphorylation also decreased with heart failure. These findings support the idea that troponin I and cMyBP-C phosphorylation promote length-dependent activation and show that length-dependent activation of contraction is blunted, yet extant, in the myocardium from patients with ischemic heart failure and further reduced in the myocardium from patients with non-ischemic heart failure. Patients who have a non-ischemic disease may exhibit a diminished contractile response to increased ventricular filling.
... As a consequence, when using experimental data to calibrate the model, all variability with the sarcomere length is projected onto the filaments activation levels. It has been shown experimentally that the peak [Ca 2+ ] i is not affected by sarcomere length and so is thus our calibrated thin filament activation level at the peak of the twitch contraction [68,69]. However, in the relaxation phase, variations of the order of 10% may appear in the case of a 7 times reduction of the force [69]. ...
Muscle contraction is triggered by the activation of the actin sites of the thin filament by calcium ions. It results that the thin filament activation level varies over time. Moreover, this activation process is also used as a regulation mechanism of the developed force. Our objective is to build a model of varying actin site activation level within the classical Huxley'57 two‐state framework. This new model is obtained as an enhancement of a previously proposed formulation of the varying thick filament activation within the same framework [1]. We assume that the state of an actin site depends on whether it is activated and whether it forms a cross‐bridge with the associated myosin head, which results in four possible states. The transitions between the actin site states are controlled by the global actin sites activation level and the dynamics of these transitions is coupled with the attachment‐detachment process. A preliminary calibration of the model with experimental twitch contraction data obtained at varying sarcomere lengths is performed. This article is protected by copyright. All rights reserved.
... A segment of the skinned fiber was connected to a force transducer (Muscle Tester, World Precision Instruments) and then incubated with a N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES)-buffered solution (see below) containing 1% (vol/vol) Triton X-100 for 10 min in order to remove the membranous structures. Fiber length was adjusted to optimal length (2.5 μm) by laser diffraction as described previously [37], and the contractile properties were measured at room temperature (24 °C). ...
Background
Muscle weakness and decreased fatigue resistance are key manifestations of systemic autoimmune myopathies (SAMs). We here examined whether high-intensity interval training (HIIT) improves fatigue resistance in the skeletal muscle of experimental autoimmune myositis (EAM) mice, a widely used animal model for SAM.
Methods
Female BALB/c mice were randomly assigned to control (CNT) or EAM groups ( n = 28 in each group). EAM was induced by immunization with three injections of myosin emulsified in complete Freund’s adjuvant. The plantar flexor (PF) muscles of mice with EAM were exposed to either an acute bout or 4 weeks of HIIT (a total of 14 sessions).
Results
The fatigue resistance of PF muscles was lower in the EAM than in the CNT group ( P < 0.05). These changes were associated with decreased activities of citrate synthase and cytochrome c oxidase and increased expression levels of the endoplasmic reticulum stress proteins (glucose-regulated protein 78 and 94, and PKR-like ER kinase) ( P < 0.05). HIIT restored all these alterations and increased the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and the mitochondrial electron transport chain complexes (I, III, and IV) in the muscles of EAM mice ( P < 0.05).
Conclusions
HIIT improves fatigue resistance in a SAM mouse model, and this can be explained by the restoration of mitochondria oxidative capacity via inhibition of the ER stress pathway and PGC-1α-mediated mitochondrial biogenesis.
... A segment of the skinned ber was connected to a force transducer (Muscle tester, World Precision Instruments) and then incubated with a N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffered solution (see below) containing 1% (vol/vol) Triton X-100 for 10 min in order to remove membranous structures. Fiber length was adjusted to optimal length (2.5 μm) by laser diffraction as described previously [37] and the contractile properties were measured at room temperature (24°C). ...
Background
Muscle weakness and decreased fatigue resistance are key manifestations of idiopathic inflammatory myopathies (IIMs). We here examined whether high-intensity interval training (HIIT) improves fatigue resistance in skeletal muscle of experimental autoimmune myositis (EAM) mice, a widely used animal model for IIM.
Methods
Female BALB/c mice were randomly assigned to control (CNT) or EAM groups (n = 28 in each group). EAM was induced by immunization with three injections of myosin emulsified in complete Freund’s adjuvant. The plantar flexor (PF) muscles from mice with EAM were exposed to either an acute bout or 4 weeks of HIIT (a total of 14 sessions).
Results
The fatigue resistance of PF muscles was lower in the EAM than in the CNT group (P < 0.05). These changes were associated with decreased activities of citrate synthase and cytochrome c oxidase and increased expression levels of the endoplasmic reticulum stress proteins (glucose-regulated protein 78 and 94, and PKR-like ER kinase) (P < 0.05). HIIT restored all these alterations and increased the peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) and the mitochondrial electron transport chain complexes (I, III, and IV) in muscles from EAM mice (P < 0.05).
Conclusions
HIIT improves fatigue resistance in an IIM mouse model and this can be explained by restoration of mitochondria oxidative capacity via inhibition of the ER stress pathway and PGC-1α-mediated mitochondrial biogenesis.
... (Allen and Kentish, 1985;Farman et al., 2010;Campbell, 2011;Sagawa et al., 1988;de Tombe et al., 2010). Length-dependent changes in calcium handling contribute to the response (Fabiato and Fabiato, 1975;Parmley and Chuck, 1973;Vahl et al., 1998;Allen and Kurihara, 1982;Kentish et al., 1986), but the primary mechanisms driving the Frank-Starling relationship probably stem from the myofilaments (i.e., the thick filaments of myosin and thin filaments of actin that are responsible for myocardial force production; Farman et al., 2010;Hibberd and Jewell, 1982;Smith et al., 2009;Cazorla et al., 2001;McDonald and Moss, 1995;Milani-Nejad et al., 2015;Hanft and McDonald, 2010). As chemically permeabilized cardiac cells are stretched, they become more sensitive to Ca 2+ and develop more force. ...
... However, there are limited data on how this process is altered during concentric CCs of moderate contractile speed (Batista et al., 2007;Baudry & Duchateau, 2004;Seitz et al., 2015). In a variety of preparations of both cardiac and skeletal muscle, it has consistently been shown that concentric contractions have differing Ca 2+ and cross-bridge kinetics compared to isometric contractions (Allen & Kurihara, 1982;Ashley & Moisescu, 1975;Caputo et al., 1994;Edman, 1996;Gordon & Ridgway, 1987;Housmans et al., 1983;Lab et al., 1984;Vandenboom et al., 1998). Specifically, during step release-induced muscle shortening there is an increase of Ca 2+ within the myoplasm due to a reduction in Ca 2+ affinity to troponin C (Edman, 1996;Stephenson & Wendt, 1984;Vandenboom et al., 1998). ...
New findings:
What is the central question of this study? To understand the effect of concentric contractions in inducing post-activation potentiation (PAP) in humans. Is the degree of PAP affected by different muscle shortening velocities? Studies have explored PAP following isometric contractions, but there is limited understanding of PAP responses following active changes in shortening speed. What are the main findings and their importance? The PAP response following maximal concentric contractions was independent of velocity. Slow and moderate velocity maximal contractions produced PAP responses like those from maximal isometric contractions when matched for contraction duration. Despite contraction type differences in cross-bridge and Ca2+ kinetics, maximal contractions, regardless of contraction modality, likely generate sufficient Ca2+ to induce maximal PAP.
Abstract:
Post-activation potentiation (PAP) is the acute enhancement of contractile properties following a brief (<10s) high intensity contraction. Compared with isometric contractions, little is known about the PAP response induced by concentric conditioning contractions (CCs) and the effect of velocity. In the dorsiflexors of 11 participants, twitch responses were measured following 5s of maximal effort concentric CCs at each of 10, 20 and 50°/s. Concentric PAP responses were compared to a maximal isometric voluntary contraction (MVC) matched for contraction time. Additionally, concentric CCs were compared to isometric CCs matched for mean torque, contraction area and time. The PAP response following maximal concentric CCs was independent of velocity and there was no difference in the PAP response between concentric CCs and an isometric MVC. During maximal contractions, regardless of contraction modality, there is likely sufficient Ca2+ to induce a similar full PAP response, and thus there was no difference between speeds or contraction type. Following concentric CCs there was a significantly larger peak twitch torque than following their isometric torque matches (49-58%), and faster maximal rates of torque development at the three speeds (62-77%). However, these responses are likely related to greater EMG in concentric contractions, 125-129% of isometric maximum compared to 38-54%, and not to contraction modality per se. Thus, PAP responses following maximal concentric CCs are not affected by velocity and responses are not different from an isometric MVC. This indicates maximal CCs of 5s produce a maximal PAP response independent of contraction type (isometric vs concentric) or shortening velocity. This article is protected by copyright. All rights reserved.
... It was still worth mentioning that Burns and Tam [5] introduced the midsole thickness as the main footwear characteristic that has advantages to improve running performance. Increasing the midsole thickness could protonate the effective leg length of the runner such as the VF shoe which has a 31 mm heel height [20]. It could decrease energy loss for the runner by increasing an 8 mm effective leg length [21,22]. ...
In this paper, to investigate the independent effect of the construction of the forefoot carbon-fiber plate inserted to the midsole on running biomechanics and finite element simulation, fifteen male marathon runners were arranged to run across a runway with embedded force plates at two specific running speeds (fast-speed: 4.81 ± 0.32 m/s, slow-speed: 3.97 ± 0.19 m/s) with two different experimental shoes (a segmented forefoot plate construction (SFC), and a full forefoot plate construction (FFC)), simulating the different pressure distributions, energy return, and stiffness during bending in the forefoot region between the SFC and FFC inserted to midsole. Kinetics and joint mechanics were analyzed. The results showed that the footwear with SFC significantly increased the peak metatarsophalangeal joint (MTPJ) plantarflexion velocity and positive work at the knee joint compared to the footwear with FFC. The results about finite element simulation showed a reduced maximum pressure on the midsole; meanwhile, not significantly affected was the longitudinal bending stiffness and energy return with the SFC compared to the FFC. The results can be used for the design of marathon running shoes, because changing the full carbon fiber plate to segment carbon fiber plate induced some biomechanical transformation but did not significantly affect the running performance, what is more, reducing the peak pressure of the carbon plate to the midsole by cutting the forefoot area of the carbon fiber plate could be beneficial from a long-distance running perspective for manufacturers.
... They were found to be permeable to ions and cations and several years later, these channels have also been identified in cardiomyocytes (Craelius et al. [40]; Hu and Sachs [94]; Reed et al. [205]). Stretch-dependent changes of the Ca 2+ handling describes modifications of the troponin C affinity for Ca 2+ (Allen and Kurihara [4]), the peak systolic intracellular Ca 2+ concentration (Allen and Kentish [3]), the diastolic intracellular Ca 2+ concentration (White et al. [260]), and the Ca 2+ storage capacity of the sarcoplasmic reticulum (Gamble et al. [71]). This affects the action potential but also the stress generation itself, which gives rise to the Frank-Starling effect at the organ scale, where an increase in the end-diastolic volume is associated with an increase in the ejected blood volume. ...
Numerous drugs had to be removed from the market because of their potential to induce the life-threatening ventricular tachyarrhythmia Torsades de Pointes (TdP). To prevent potentially torsadogenic drugs to enter the market, a detailed safety assessment in drug development is of utmost importance. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative has been founded in order to develop a mechanistic-based approach for TdP risk predictions in safety assessments. Central component is a mathematical model of cardiomyocyte electrophysiology that is used to predict the TdP risk based on an electrophysiological biomarker. Then, unanticipated drug effects are evaluated in human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) cultures before the evaluation continues in humans in the phase 1 clinical trials. The action potential triggers mechanical contraction through the mechanisms of excitation contraction coupling but the mechanics has widely been neglected in studies dealing with TdP risk prediction.
This thesis describes the development of a mathematical model of the electromechanics in hiPSC-derived cell cultures. In the first study, it was applied to investigate whether the TdP risk of drugs can also be predicted using mechanical biomarkers. To this end, the mathematical model was fitted to experiments with the novel FLEXcyte96 technology that has been developed to analyse the contraction-relaxation cycle in hiPSC-derived cell cultures. Ten drugs of the CiPA reference set with known TdP risk were considered in the study and mechanical drug effects were analysed by twelve biomarkers of the contraction-relaxation cycle. Three biomarkers were found that could differentiate the drugs by their known TdP risk and are suggested to be further examined in studies with a larger number of drugs.
To improve the translation of hiPSC-CMs studies to humans, it is required to engineer hiPSC-derived cardiac cell cultures that resemble regions of the undiseased and diseased human heart as good as possible. The heart is not only made up by cardiomyocytes but also by a large number of cardiac fibroblasts. Cardiac fibroblasts are able to modify cardiac electrophysiology but this has not yet been studied comprehensively in hiPSCderived cardiac cell cultures. In the second study, the effects of human induced pluripotent stem cell-derived cardiac fibroblasts (hiPSC-CFs) on hiPSC-CM electrophysiology were investigated in two-dimensional co-cultures. This was done based on microelectrode array (MEA) experiments and using the mathematical model that was fitted to these experiments. The observed electrophysiological effects were in wide agreement with those found in animal cell cultures and demonstrate the capability of hiPSC-derived cardiac fibroblasts to modify hiPSC-CM electrophysiology in co cultures. In addition, it was found that modifications of the electrophysiology are associated with modifications of the contraction-relaxation cycle.
... One prediction of the model was that that stretching just prior to the action potential, such as that which might occur by the filling of the ventricles, optimally potentiates action potential-induced Ca 2+ release. In fact, in cardiac myocytes, stretching has been shown to increase the magnitude of the Ca 2+ and force transients during pacing [7,8]. ...
The stretching of a cardiomyocyte leads to the increased production of reactive oxygen species that increases ryanodine receptor open probability through a process termed X-ROS signaling. The stretching of the myocyte also increases the calcium affinity of myofilament Troponin C, which increases its calcium buffering capacity. Here, an integrative experimental and modeling study is pursued to explain the interplay of length-dependent changes in calcium buffering by troponin and stretch-activated X-ROS calcium signaling. Using this combination, we show that the troponin C-dependent increase in myoplasmic calcium buffering during myocyte stretching largely offsets the X-ROS-dependent increase in calcium release from the sarcoplasmic reticulum. The combination of modeling and experiment are further informed by the elimination of length-dependent changes to troponin C calcium binding in the presence of blebbistatin. Here, the model suggests that it is the X-ROS signaling-dependent Ca2+ release increase that serves to maintain free myoplasmic calcium concentrations during a change in myocyte length. Together, our experimental and modeling approaches have further defined the relative contributions of X-ROS signaling and the length-dependent calcium buffering by troponin in shaping the myoplasmic calcium transient.
... The stretch-dependent changes in the cardiac contraction force have biphasic properties: first, a rapid and larger increase in force, and second, a slow increase in force [138,139]. Stretching of the ventricle and atrium is accompanied by increases in Ca 2+ transient amplitude [140][141][142]. Stretch-induced augmentation of Ca 2+ transients may result from enhanced unitary Ca 2+ releases in ventricular myocytes. ...
Homeostasis in the level of reactive oxygen species (ROS) in cardiac myocytes plays a critical role in regulating their physiological functions. Disturbance of balance between generation and removal of ROS is a major cause of cardiac myocyte remodeling, dysfunction, and failure. Cardiac myocytes possess several ROS-producing pathways, such as mitochondrial electron transport chain, NADPH oxidases, and nitric oxide synthases, and have endogenous antioxidation mechanisms. Cardiac Ca2+-signaling toolkit proteins, as well as mitochondrial functions, are largely modulated by ROS under physiological and pathological conditions, thereby producing alterations in contraction, membrane conductivity, cell metabolism and cell growth and death. Mechanical stresses under hypertension, post-myocardial infarction, heart failure, and valve diseases are the main causes for stress-induced cardiac remodeling and functional failure, which are associated with ROS-induced pathogenesis. Experimental evidence demonstrates that many cardioprotective natural antioxidants, enriched in foods or herbs, exert beneficial effects on cardiac functions (Ca2+ signal, contractility and rhythm), myocytes remodeling, inflammation and death in pathological hearts. The review may provide knowledge and insight into the modulation of cardiac pathogenesis by ROS and natural antioxidants.
... There has been considerable research exploring the mechanisms underlying the Frank-Starling relationship, yet the molecular mechanisms remain elusive. It is evident that following a change in length of cardiac muscle, there is a significant alteration in the calcium (Ca 2+ ) sensitivity of force (Allen and Kurihara, 1982), i.e., changes in the responsiveness of the myofilaments to Ca 2+ (reviewed in Fuchs and Martyn, 2005). Length-dependent changes in the activation of cardiac myofilaments appear to occur within a few milliseconds of the length change (Mateja and de Tombe, 2012), which implies that the length change induces a strain-dependent rearrangement of the thick and thin filament lattice and/or individual contractile and regulatory proteins. ...
The Frank–Starling relationship establishes that elevated end-diastolic volume progressively increases ventricular pressure and stroke volume in healthy hearts. The relationship is modulated by a number of physiological inputs and is often depressed in human heart failure. Emerging evidence suggests that cardiac myosin-binding protein-C (cMyBP-C) contributes to the Frank–Starling relationship. We measured contractile properties at multiple levels of structural organization to determine the role of cMyBP-C and its phosphorylation in regulating (1) the sarcomere length dependence of power in cardiac myofilaments and (2) the Frank–Starling relationship in vivo. We compared transgenic mice expressing wild-type cMyBP-C on the null background, which have ∼50% phosphorylated cMyBP-C (Controls), to transgenic mice lacking cMyBP-C (KO) and to mice expressing cMyBP-C that have serine-273, -282, and -302 mutated to aspartate (cMyBP-C t3SD) or alanine (cMyBP-C t3SA) on the null background to mimic either constitutive PKA phosphorylation or nonphosphorylated cMyBP-C, respectively. We observed a continuum of length dependence of power output in myocyte preparations. Sarcomere length dependence of power progressively increased with a rank ordering of cMyBP-C KO = cMyBP-C t3SA < Control < cMyBP-C t3SD. Length dependence of myofilament power translated, at least in part, to hearts, whereby Frank–Starling relationships were steepest in cMyBP-C t3SD mice. The results support the hypothesis that cMyBP-C and its phosphorylation state tune sarcomere length dependence of myofibrillar power, and these regulatory processes translate across spatial levels of myocardial organization to control beat-to-beat ventricular performance.
... The slow force response (SFR) to myocardial stretch is a second increase in developed force that occurs just after the Frank-Starling mechanism takes place. It is well-known that an augmented calcium transient amplitude underlies its development (1,2) but the exact genesis of this increase is still a matter of debate. We have proposed that the SFR is the mechanical expression of a stretchtriggered autocrine mechanism where oxidative stress targeting the Na + /H + exchanger (NHE1) plays a crucial role (3). ...
The stretch of cardiac muscle increases developed force in two phases. The first phase occurs immediately after stretch and is the expression of the Frank–Starling mechanism, while the second one or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude. An important step in the chain of events leading to the SFR generation is the increased production of reactive oxygen species (ROS) leading to redox sensitive ERK1/2, p90RSK, and NHE1 phosphorylation/activation. Conversely, suppression of ROS production blunts the SFR. The purpose of this study was to explore whether overexpression of the ubiquitously expressed antioxidant molecule thioredoxin-1 (TRX1) affects the SFR development and NHE1 phosphorylation. We did not detect any change in basal phopho-ERK1/2, phopho-p90RSK, and NHE1 expression in mice with TRX1 overexpression compared to wild type (WT). Isolated papillary muscles from WT or TRX1-overexpressing mice were stretched from 92 to 98% of its maximal length. A prominent SFR was observed in WT mice that was completely canceled in TRX1 animals. Interestingly, myocardial stretch induced a significant increase in NHE1 phosphorylation in WT mice that was not detected in TRX1-overexpressing mice. These novel results suggest that magnification of cardiac antioxidant defense power by overexpression of TRX1 precludes NHE1 phosphorylation/activation after stretch, consequently blunting the SFR development.
... These responses in the intact heart have been respectively described as the Frank-Starling law and the Anrep effect for over 100 years [2][3][4] , which constitute powerful mechanisms to allow the heart to adapt to an abrupt rise in either preload or afterload. While the Frank-Starling phenomenon is in part due to a sensitization of the myofibrillar Ca 2+ sensitivity 5,6 , an increase in intracellular Ca 2+ might play a key role in mediating the stretch-induced biphasic enhancement of cardiac contraction 7,8 . It has been proposed that stretch-activated cation channels might provide a conceptually simple mechanism for conferring cardiac mechanosensitivity and the resulting Ca 2+ signaling 9,10 , which determines the strength of cardiac contraction 11 . ...
The beating heart possesses the intrinsic ability to adapt cardiac output to changes in mechanical load. The century-old Frank–Starling law and Anrep effect have documented that stretching the heart during diastolic filling increases its contractile force. However, the molecular mechanotransduction mechanism and its impact on cardiac health and disease remain elusive. Here we show that the mechanically activated Piezo1 channel converts mechanical stretch of cardiomyocytes into Ca ²⁺ and reactive oxygen species (ROS) signaling, which critically determines the mechanical activity of the heart. Either cardiac-specific knockout or overexpression of Piezo1 in mice results in defective Ca ²⁺ and ROS signaling and the development of cardiomyopathy, demonstrating a homeostatic role of Piezo1. Piezo1 is pathologically upregulated in both mouse and human diseased hearts via an autonomic response of cardiomyocytes. Thus, Piezo1 serves as a key cardiac mechanotransducer for initiating mechano-chemo transduction and consequently maintaining normal heart function, and might represent a novel therapeutic target for treating human heart diseases.
... Novel techniques such as the cell-in-gel system (254) also allowed the application of stress during cardiomyocyte contraction and the measurement of calcium and stress properties. Other experiments altering mechanical load and electrical stimuli, such as quick-release protocols (255) or force frequency (256) experiments, have also highlighted the bidirectionality of electromechanical interactions. Imaging techniques such as confocal microscopy (257), optical mapping (258), and more recently 3-dimensional super-resolution imaging (164) have made it possible to visualize the structures involved. ...
[CLICK DOI ABOVE TO GET THE FREE FULLTEXT] Cardiomyocyte calcium handling is a major determinant of excitation-contraction coupling. Alterations in one or more calcium-handling proteins may induce arrhythmias through the formation of ectopic activity, direct and indirect ion-channel regulation, and structural remodeling. Due to the complex and tight interactions between calcium and other molecules within a cardiomyocyte, it remains experimentally challenging to study the exact contributions of calcium-handling abnormalities to arrhythmogenesis. Multiscale computational studies performed in close collaboration with laboratory experiments create new opportunities to unravel the mechanisms of arrhythmogenesis. This thesis describes the roles of integrative computational modeling in unraveling the arrhythmogenic consequences of calcium- handling abnormalities.
... On the contrary, the heart has an elastic modulus of at ≈20 kPa, which is significantly higher than that of the brain, and experiences periodic volumetric expansion/shrinkage of ≈10%. [31,32] Furthermore, cardiovascular diseases can increase the stiffness of heart tissues by a factor of 2-3. [33] Therefore, cardiac devices need to possess stretchability that is compatible to the cardiac motions and microenvironmental changes. ...
Implantable biosensors and wearable bioelectronics need to be intimately interfaced with soft human tissues for a high‐quality health diagnosis and feedback therapy. Despite the recent developments in these devices, it is essential to further enhance their performance and functionalities in order to facilitate the formation of intimate interfaces between the devices and the human body. This will help minimize the unwanted injuries to target tissues, enhance the efficiency of sensing and therapy, and achieve long‐term biocompatibility. In this regard, the physiological and mechanical properties of the target tissues need to be considered carefully when designing the materials and devices to be employed in implantable and wearable electronics. Herein, a discussion of the recent developments in implantable biosensors and wearable electronics, based on unconventional device designs and material approaches, is presented. This review particularly focuses on the design principles of devices and materials that enable an intimate integration of biosensing devices with soft tissues and target organs. In addition, recent developments of electronics employed in stand‐alone wearable biomedical systems, such as wearable displays and energy devices, are presented. Moreover, future prospects for emerging approaches that could enable further developments of implantable biosensors and wearable electronics are also discussed.
... This stretch-induced increase in SR Ca 2ϩ release may be especially important in acute ischemia as it is enhanced, along with the stretch-induced increase in ROS production, in that setting (90). Intracellular free Ca 2ϩ is also acutely affected by a length-dependent change in the affinity of troponin C (TnC) for Ca 2ϩ (4), such that with increased stretch (4,6) or tension (685), more Ca 2ϩ is in the bound state. Upon rapid shortening, the dissociation of Ca 2ϩ from TnC causes a surge in intracellular Ca 2ϩ (638). ...
The heart is vital for biological function in almost all chordates, including human. It beats continually throughout our life, supplying the body with oxygen and nutrients while removing waste products. If it stops - so does life. The heartbeat involves precise coordination of the activity of billions of individual cells, as well as their swift and well-coordinated adaption to changes in physiological demand. Much of the vital control of cardiac function occurs at the level of individual cardiac muscle cells, including acute beat-by-beat feedback from the local mechanical environment to electrical activity (as opposed to longer-term changes in gene expression, and functional or structural remodelling). This process is known as Mechano-Electric Coupling (MEC). In the current review, we: present evidence for, and implications of, MEC in health and disease in human; summarise our understanding of MEC effects gained from whole animal, organ, tissue, and cell studies; identify potential molecular mediators of MEC responses; and demonstrate the power of computational modelling in developing a more comprehensive understanding of 'what makes the heart tick'.
... Novel techniques such as the cell-in-gel system (Jian et al., 2014) also allowed the application of stress during cardiomyocyte contraction and the measurement of Ca 2þ and stress properties. Other experiments altering mechanical load and electrical stimuli, such as quick-release protocols (Allen and Kurihara, 1982) or force frequency (Mulieri et al., 1992) experiments, have also highlighted the bidirectionality of electromechanical interactions. Imaging techniques such as confocal microscopy (Balnave et al., 1997), optical mapping (Jaimes et al., 2016), and more recently 3dimensional super-resolution imaging (Shen et al., 2019) have made it possible to visualize the structures involved. ...
Calcium (Ca2+) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca2+ levels are regulated by a variety of Ca2+-handling proteins. In turn, Ca2+ modulates numerous electrophysiological processes. Accordingly, Ca2+-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including the promotion of afterdepolarizations, ion-channel modulation and structural remodeling. In the last 30 years, significant improvements have been made in the computational modeling of cardiomyocyte Ca2+ handling under physiological and pathological conditions. However, numerous questions involving the Ca2+-dependent regulation of different macromolecular complexes, cross-talk between Ca2+-dependent regulatory pathways operating over a wide range of time scales, and bidirectional interactions between electrophysiology and mechanics remain to be addressed by in vitro and in silico studies. A better understanding of disease-specific Ca2+-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca2+ handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca2+ handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca2+ handling and highlight how synergy between in vitro and in silico studies may help to answer several of these issues.
... It has since been proposed that this "Slow Force Response (SFR)" (Figure 1, SFR) is the in vitro equivalent of the Anrep effect (Alvarez et al., 1999). Unlike the Frank-Starling mechanism, SFR is induced by a gradual increase in Ca 2+ transient amplitude (Allen and Kurihara, 1982;Kentish and Wrzosek, 1998) through the activation of multiple intracellular components and ion transporters (Cingolani et al., 2013). Notably, AT 1 R may control this signaling pathway (Cingolani et al., 2013). ...
The myocardium has an intrinsic ability to sense and respond to mechanical load in order to adapt to physiological demands. Primary examples are the augmentation of myocardial contractility in response to increased ventricular filling caused by either increased venous return (Frank–Starling law) or aortic resistance to ejection (the Anrep effect). Sustained mechanical overload, however, can induce pathological hypertrophy and dysfunction, resulting in heart failure and arrhythmias. It has been proposed that angiotensin II type 1 receptor (AT1R) and apelin receptor (APJ) are primary upstream actors in this acute myocardial autoregulation as well as the chronic maladaptive signaling program. These receptors are thought to have mechanosensing capacity through activation of intracellular signaling via G proteins and/or the multifunctional transducer protein, β-arrestin. Importantly, ligand and mechanical stimuli can selectively activate different downstream signaling pathways to promote inotropic, cardioprotective or cardiotoxic signaling. Studies to understand how AT1R and APJ integrate ligand and mechanical stimuli to bias downstream signaling are an important and novel area for the discovery of new therapeutics for heart failure. In this review, we provide an up-to-date understanding of AT1R and APJ signaling pathways activated by ligand versus mechanical stimuli, and their effects on inotropy and adaptive/maladaptive hypertrophy. We also discuss the possibility of targeting these signaling pathways for the development of novel heart failure therapeutics.
... The current study was focused on fast responses of the myocardium to mechanical impacts and, therefore, we did not deal with slow force responses such as the experimentally shown transient process that occurs during a series of contractions after a rapid increase in length. This process was observed, for example, in experiments on rat and cat myocardium preparations [76,95]. In essence, the slow force response referred to above is as follows. ...
Experiments on animal hearts (rat, rabbit, guinea pig, etc.) have demonstrated that mechano-calcium feedback (MCF) and mechano-electric feedback (MEF) are very important for myocardial self-regulation because they adjust the cardiomyocyte contractile function to various mechanical loads and to mechanical interactions between heterogeneous myocardial segments in the ventricle walls. In in vitro experiments on these animals, MCF and MEF manifested themselves in several basic classical phenomena (e.g., load dependence, length dependence of isometric twitches, etc.), and in the respective responses of calcium transients and action potentials. However, it is extremely difficult to study simultaneously the electrical, calcium, and mechanical activities of the human heart muscle in vitro. Mathematical modeling is a useful tool for exploring these phenomena. We have developed a novel model to describe electromechanical coupling and mechano-electric feedbacks in the human cardiomyocyte. It combines the 'ten Tusscher-Panfilov' electrophysiological model of the human cardiomyocyte with our module of myocardium mechanical activity taken from the 'Ekaterinburg-Oxford' model and adjusted to human data. Using it, we simulated isometric and afterloaded twitches and effects of MCF and MEF on excitation-contraction coupling. MCF and MEF were found to affect significantly the duration of the calcium transient and action potential in the human cardiomyocyte model in response to both smaller afterloads as compared to bigger ones and various mechanical interventions applied during isometric and afterloaded twitches.
... Within a physiological range of sarcomere length, developed tension increases as sarcomere length increases, or as heart muscle is stretched. The increase in developed tension is not accompanied by an increase in cytosolic Ca 2+ transients (Allen & Kurihara, 1982). The mechanisms underlying the length-force relationship are generally explained by increases in the number of cross-bridges and the affinity of the troponin complex for Ca 2+ . ...
It has been an unsolved question how cardiac mitochondrial energetics is regulated during working transition. Mathematical modelling is a powerful tool for exploring the complicated networks of mitochondrial metabolism. We summarize the recent progress and remaining questions about mitochondrial energetics in heart, especially focusing on approaches utilizing mathematical modelling. Feedback activation by ADP and/or inorganic phosphate is an old but still attractive hypothesis for explaining the regulation mechanisms of cardiac mitochondrial energetics. However, this hypothesis has not been fully validated by experiments because rises of ADP and/or inorganic phosphate concentrations during cardiac workload increase have not been detected in many experiments. The hypothesis of intracellular energetic units is an extended version of feedback activation, which has a similar problem. The each‐step activation hypothesis beautifully reproduces metabolite constancy, although such master regulators have not been identified yet. Ca²⁺ has been the most plausible candidate because some of the mitochondrial dehydrogenases are activated by it. Recent experimental and simulation studies, however, throw doubt on its physiological relevance. Finally, we discuss issues to be solved to obtain a better view of cardiac mitochondrial energetics. image
... In this work, we did not deal with slow force responses such as experimentally shown transient process that occurs during a series of contractions after a rapid increase in the length obtained, for example, in experiments on rat and cat myocardium preparations [76,88]. The essence of the referred slow force response is as follows. ...
Experiments on animal hearts (rat, rabbit, guinea pig, etc.) showed that mechano-calcium feedback (MCF) and mechano-electric feedback (MEF) are very important for myocardial self-regulation. This is because they adjust cardiomyocyte contractile function to various mechanical loads and to the mechanical interaction of heterogeneous myocardial segments in the ventricle walls. In the in vitro experiments on these animals MCF and MEF manifested themselves in several basic classic phenomena (e.g. load dependence, length dependence of isometric twitches, etc.), and in the respective responses of calcium transients and action potentials. However, simultaneous study of electrical, calcium, and mechanical activity of the human heart muscle in vitro is extremely difficult. Here we apply mathematical modeling to study these phenomena. We develop a novel model describing electromechanical coupling and mechano-electric feedbacks in the human cardiomyocyte. This model combines the 'ten Tusscher - Panfilov' electrophysiological model of the human cardiomyocyte with our module of the myocardium mechanical activity taken from the 'Ekaterinburg - Oxford' model and adjusted to human data. Using it we model isometric and isotonic twitches and study effects of MCF and MEF on the excitation-contraction coupling. We have shown that MCF and MEF both for smaller afterloads as compared to bigger ones and for various mechanical interventions during isometric and isotonic twitches substantially affect durations of calcium transient and action potential in the human cardiomyocyte model.
... A segment of the skinned fiber was connected to a force transducer (Muscle tester, World Precision Instruments) and then incubated with a N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffered solution (see below) containing the detergent Triton X-100 (1% (vol/vol), 10 min treatment) to remove all membranous structures. Fiber length was adjusted to optimal length (2.5 μm) by laser diffraction as described previously [29] and the contractile properties were measured at room temperature (24˚C). ...
Although there is good evidence to indicate a major role of intrinsic impairment of the contractile apparatus in muscle weakness seen in several pathophysiological conditions, the factors responsible for control of myofibrillar function are not fully understood. To investigate the role of mechanical load in myofibrillar function, we compared the skinned fiber force between denervated (DEN) and dexamethasone-treated (DEX) rat skeletal muscles with or without neuromuscular electrical stimulation (ES) training. DEN and DEX were induced by cutting the sciatic nerve and daily injection of dexamethasone (5 mg/kg/day) for 7 days, respectively. For ES training, plantarflexor muscles were electrically stimulated to produce four sets of five isometric contractions each day. In situ maximum torque was markedly depressed in the DEN muscles compared to the DEX muscles (-74% vs. -10%), whereas there was not much difference in the degree of atrophy in gastrocnemius muscles between DEN and DEX groups (-24% vs. -17%). Similar results were obtained in the skinned fiber preparation, with a greater reduction in maximum Ca²⁺-activated force in the DEN than in the DEX group (-53% vs. -16%). Moreover, there was a parallel decline in myosin heavy chain (MyHC) and actin content per muscle volume in DEN muscles, but not in DEX muscles, which was associated with upregulation of NADPH oxidase (NOX) 2, neuronal nitric oxide synthase (nNOS), and endothelial NOS expression, translocation of nNOS from the membrane to the cytosol, and augmentation of mRNA levels of muscle RING finger protein 1 (MuRF-1) and atrogin-1. Importantly, mechanical load evoked by ES protects against DEN- and DEX-induced myofibrillar dysfunction and these molecular alterations. Our findings provide novel insights regarding the difference in intrinsic contractile properties between DEN and DEX and suggest an important role of mechanical load in preserving myofibrillar function in skeletal muscle.
Calcium signalling underlies much of physiology. Almost all the Ca2+ in the cytoplasm is bound to buffers, with typically only about 1% being freely ionized at resting levels in most cells. Physiological Ca2+ buffers include small molecules and proteins, and experimentally, Ca2+ indicators will also buffer calcium. The chemistry of interactions between Ca2+ and buffers determines the extent and speed of Ca2+ binding. The physiological effects of Ca2+ buffers are determined by the kinetics with which they bind Ca2+ and their mobility within the cell. The degree of buffering depends on factors such as the affinity for Ca2+, the Ca2+ concentration, and whether Ca2+ ions bind cooperatively. Buffering affects both the amplitude and time course of cytoplasmic Ca2+ signals as well as changes of Ca2+ concentration in organelles. It can also facilitate Ca2+ diffusion inside the cell. Ca2+ buffering affects synaptic transmission, muscle contraction, Ca2+ transport across epithelia, and the killing of bacteria. Saturation of buffers leads to synaptic facilitation, tetanic contraction in skeletal muscle, and may play a role in inotropy in the heart. This review focuses on the link between buffer chemistry and function and how Ca2+ buffering affects normal physiology and the consequences of changes in disease. As well as summarizing what is known, we point out the many areas where further work is required.
We recently described calcium signaling in the appendicularian tunicate Oikopleura dioica during pre-gastrulation stages, and showed that regularly occurring calcium waves progress throughout the embryo in a characteristic spatiotemporal pattern from an initiation site in muscle lineage blastomeres (Mikhaleva et al., 2019). Here, we have extended our observations to the period spanning from gastrulation to post-hatching stages. We find that repetitive Ca2+ waves persist throughout this developmental window, albeit with a gradual increase in frequency. The initiation site of the waves shifts from muscle cells at gastrulation and early tailbud stages, to the central nervous system at late tailbud and post-hatching stages, indicating a transition from muscle-driven to neurally driven events as tail movements emerge. At these later stages, both the voltage gated Na + channel blocker tetrodotoxin (TTX) and the T-type Ca2+ channel blocker and nAChR antagonist mecamylamine eliminate tail movements. At late post-hatching stages, mecamylamine blocks Ca2+ signals in the muscles but not the central nervous system. Post-gastrulation Ca2+ signals also arise in epithelial cells, first in a haphazard pattern in scattered cells during tailbud stages, evolving after hatching into repetitive rostrocaudal waves with a different frequency than the nervous system-to-muscle waves, and insensitive to mecamylamine. The desynchronization of Ca2+ waves arising in different parts of the body indicates a shift from whole-body to tissue/organ-specific Ca2+ signaling dynamics as organogenesis occurs, with neurally driven Ca2+ signaling dominating at the later stages when behavior emerges.
Three dimensional (3D) printing of heart patches usually provides the ability to precisely control cell location in 3D space. Here, one‐step 3D printing of cardiac patches with built‐in soft and stretchable electronics is reported. The tissue is simultaneously printed using three distinct bioinks for the cells, for the conducting parts of the electronics and for the dielectric components. It is shown that the hybrid system can withstand continuous physical deformations as those taking place in the contracting myocardium. The electronic patch is flexible, stretchable, and soft, and the electrodes within the printed patch are able to monitor the function of the engineered tissue by providing extracellular potentials. Furthermore, the system allowed controlling tissue function by providing electrical stimulation for pacing. It is envisioned that such transplantable patches may regain heart contractility and allow the physician to monitor the implant function as well as to efficiently intervene from afar when needed. The one‐step 3D printing of cardiac patches with built‐in soft and stretchable electronics is reported. The tissue is printed using three distinct bioinks for the cells and the conducting and dielectric parts of the electronics. The electrodes within the printed patch can monitor the function of the engineered tissue, and control tissue function by providing electrical stimulation for pacing.
Elastomers are suitable materials for constructing a conformal interface with soft and curvilinear biological tissue due to their intrinsically deformable mechanical properties. Intrinsically soft electronic devices whose mechanical properties are comparable to human tissue can be fabricated using suitably functionalized elastomers. This article reviews recent progress in functionalized elastomers and their application to intrinsically soft and biointegrated electronics. Elastomers can be functionalized by adding appropriate fillers, either nanoscale materials or polymers. Conducting or semiconducting elastomers synthesized and/or processed with these materials can be applied to the fabrication of soft biointegrated electronic devices. For facile integration of soft electronics with the human body, additional functionalization strategies can be employed to improve adhesive or autonomous healing properties. Recently, device components for intrinsically soft and biointegrated electronics, including sensors, stimulators, power supply devices, displays, and transistors, have been developed. Herein, representative examples of these fully elastomeric device components are discussed. Finally, the remaining challenges and future outlooks for the field are presented.
The heart rhythm is maintained by oscillatory changes in [Ca²⁺]. However, it has been suggested that the rapid drop in blood pressure that occurs with a slow decrease in [Ca²⁺] preceding early diastolic filling is related to the mechanism of rapid sarcomere lengthening associated with spontaneous tension oscillation at constant intermediate [Ca²⁺]. Here, we analyzed a new type of oscillation called hyperthermal sarcomeric oscillation. Sarcomeres in rat neonatal cardiomyocytes that were warmed at 38–42 °C oscillated at both slow (~ 1.4 Hz), Ca²⁺-dependent frequencies and fast (~ 7 Hz), Ca²⁺-independent frequencies. Our high-precision experimental observations revealed that the fast sarcomeric oscillation had high and low peak-to-peak amplitude at low and high [Ca²⁺], respectively; nevertheless, the oscillation period remained constant. Our numerical simulations suggest that the regular and fast rthythm is maintained by the unchanged cooperative binding behavior of myosin molecules during slow oscillatory changes in [Ca²⁺].
Aims:
Cardiac electrophysiology and mechanics are strongly interconnected. Calcium is crucial in this complex interplay through its role in cellular electrophysiology and sarcomere contraction. We aim to differentiate the effects of acute β-adrenergic stimulation (β-ARS) and cardiomyocyte stretch (increased sarcomere length) on calcium-transient dynamics and force generation, using a novel computational model of cardiac electromechanics.
Methods:
We implemented a bidirectional coupling between the O'Hara-Rudy model of human ventricular electrophysiology and the MechChem model of sarcomere mechanics through the buffering of calcium by troponin. The coupled model was validated using experimental data from large mammals or human samples. Calcium transient and force were simulated for various degrees of β-ARS and initial sarcomere lengths.
Results:
The model reproduced force-frequency, quick-release and isotonic contraction experiments, validating the bidirectional electromechanical interactions. An increase in β-ARS increased the amplitudes of force (augmented inotropy) and calcium transient, and shortened both force and calcium-transient duration (lusitropy). An increase in sarcomere length increased force amplitude even more, but decreased calcium-transient amplitude and increased both force and calcium-transient duration. Finally, a gradient in relaxation along the thin filament may explain the non-monotonic decay in cytosolic calcium observed with high tension.
Conclusions:
Using a novel coupled human electromechanical model, we identified differential effects of β-ARS and stretch on calcium and force. Stretch mostly contributed to increased force amplitude and β-ARS to the reduction of calcium and force duration. We showed that their combination, rather than individual contributions, is key to ensure force generation, rapid relaxation, and low diastolic calcium levels.
Reactive cardiac hypertrophy (CH) is an increase in heart mass in response to hemodynamic overload. Exercise-induced CH emerges as an adaptive response with improved cardiac function, in contrast to pathological CH that represents a risk factor for cardiovascular health.
The Na⁺/H⁺ exchanger (NHE-1) is a membrane transporter that not only regulates intracellular pH but also intracellular Na⁺ concentration. In the scenario of cardiovascular diseases, myocardial NHE-1 is activated by a variety of stimuli, such as neurohumoral factors and mechanical stress, leading to intracellular Na⁺ overload and activation of prohypertrophic cascades. NHE-1 hyperactivity is intimately linked to heart diseases, including ischemia-reperfusion injury, maladaptive CH and heart failure.
In this review, we will present evidence to support that the NHE-1 hyperactivity constitutes a “switch on/off” for the pathological phenotype during CH development. We will also discuss some classical and novel strategies to avoid NHE-1 hyperactivity, and that are therefore worthwhile to improve cardiovascular health.
Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy and is mainly caused by mutations of genes encoding cardiac sarcomeric proteins. HCM is characterized by hypertrophy of the left ventricle, frequently involving the septum, that is not explained solely by loading conditions. HCM has a heterogeneous clinical profile, but diastolic dysfunction and ventricular arrhythmias represent two dominant features of the disease. Preclinical evidence indicates that the enhanced Calcium (Ca2+) sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric mutations, but can also result from secondary mutation‐driven alterations. Here, we review experimental and clinical evidence indicating that increased myofilament Ca2+ sensitivity lies upstream of numerous cellular derangements which potentially contribute to the progression of HCM toward heart failure and sudden cardiac death. This article is protected by copyright. All rights reserved.
Patients with rheumatoid arthritis (RA) frequently suffer from muscle weakness. We examined whether eccentric training prevents skeletal muscle weakness in adjuvant-induced arthritis (AIA) rat, a widely used animal model for RA. AIA was induced in the knees of Wistar rats by injection of complete Freund's adjuvant. To induce eccentric contractions (ECCs), neuromuscular electrical stimulation (45 V) was applied to the plantar flexor muscles simultaneously with forced dorsiflexion of the ankle joint (0-40˚) and was given every 6 s. ECC exercise was applied every other day for a total of 11 sessions and consisted of 4 sets of 5 contractions. There was a significant reduction in in vitro maximum Ca2+-activated force in skinned fibers in gastrocnemius muscle from AIA rats. These changes were associated with reduced expression levels of contractile proteins (i.e., myosin and actin), increased levels of inflammation-redox stress-related biomarkers (i.e., TNF-α, malondialdehyde-protein adducts, NADPH oxidase 2, and neuronal nitric oxide synthase), and autolyzed active calpain-1 in AIA muscles. ECC training markedly enhanced the steady-state levels of αB-crystallin, a small heat shock protein, and its binding to the myofibrils and prevented the AIA-induced myofibrillar dysfunction, reduction in contractile proteins, and inflammation-oxidative stess insults. Our findings demonstrate that ECC training preserves myofibrillar function without muscle damage in AIA rats, which is at least partially attributable to the protective effect of αB-crystallin on the myofibrils against oxidative stress-mediated protein degeneration. Thus, ECC training can be a safe and effective intervention counteracting the loss of muscle strength in RA patients.
Replacement of the damaged scar tissue created by a myocardial infarction is the goal of cardiac tissue engineering. However, once the implanted tissue is in place, monitoring its function is difficult and involves indirect methods, while intervention necessarily requires an invasive procedure and available medical attention. To overcome this, methods of integrating electronic components into engineered tissues have been recently presented. These allow for remote monitoring of tissue function as well as intervention through stimulation and controlled drug release. Here, an improved hybrid microelectronic tissue construct capable of withstanding the dynamic environment of the beating heart without compromising electronic or mechanical functionality is reported. While the reported system is enabled to sense the function of the engineered tissue and provide stimulation for pacing, an electroactive polymer on the electronics enables it to release multiple drugs in parallel. It is envisioned that the integration of microelectronic devices into engineered tissues will provide a better way to monitor patient health from afar, as well as provide facile, more exact methods to control the healing process.
High temperature shortens cardiac contraction time and relaxation time, and low temperature extends them. Goodness of half-logistic (h-L) function fits are superior to goodness of mono-exponential (m-E) function fits for the four phases; the first half of the ascending phase, second half of the ascending phase, first half of the descending phase, and second half of the descending phase of the isovolumic left ventricular pressure-time curve in the excised, cross-circulated canine heart at any temperatures. Four h-L time constants obtained by the h-L curve fittings extend with decreasing temperature and shorten with increasing temperature. Moreover, goodness of h-L function fits are superior to goodness of m-E function fits for the four phases of the isometric force-time curve and intracellular free calcium transient-time curve observed in the rat right ventricular papillary muscle and mouse left ventricular papillary muscle at low temperature. Four h-L time constants can be indices to evaluate cardiac or myocardial inotropic and lusitropic functions, and contraction process and relaxation process of intracellular free calcium transient accurately regardless of change in temperature.
An ultimate test of theories of muscle contraction is to reproduce contractile behaviour as a function of the sarcoplasmic concentration of calcium ions. In muscle, the cooperative nature of Ca²⁺-activation seen with regulated actin in solution is manifest in the steep rise of isometric tension and ATPase rate with [Ca²⁺], and also in the regulation of transient responses. This chapter surveys the wealth of behaviour observed in striated muscle, fibres, myofibrils and motility assays, before turning to theories of cooperative regulation in fibres. For a single thin filament, a lattice theory of cooperative activation with TmTn units as a continuous flexible chain is developed, and explored computationally with a simple crossbridge model. Spontaneous oscillatory contractions (SPOC) constitute a new state of muscle observed only at low calcium, which can be modelled in terms of enhanced length activation on the descending limb. Finally, we consider direct myosin regulation by its light chains, and whether this mechanism can act cooperatively.
During partial Ca2+ activation, skinned cardiac cells with sarcoplasmic reticulum destroyed by detergent developed spontaneous tension oscillations consisting of cycles (0.1-1 Hz) of rapid decrease of tension corresponding to the yield of some sarcomeres and slow redevelopment of tension corresponding to the reshortening of these sarcomeres. Such myofilament-generated tension oscillations were never observed during the full activation induced by a saturating [free Ca2+] or during the rigor tension induced by decreasing [MgATP] in the absence of free Ca2+ or when the mean sarcomere length (SL) of the preparation was greater than 3.10 microm during partial Ca2+ activation. A stiff parallel elastic element borne by a structure that could be digested by elastase hindered the study of the SL--active tension diagram in 8-13-microm-wide skinned cells from the rat ventricle, but this study was possible in 2-7-microm-wide myofibril bundles from the frog or dog ventricle. During rigor the tension decreased linearly when SL was increased from 2.35 to 3.80 microm. During full Ca2+ activation the tension decreased by less than 20% when SL was increased from 2.35 to approximately 3.10 microm. During partial Ca2+ activation the tension increased when SL was increased from 2.35 to 3.00 microm. From this observation of an apparent increase in the sensitivity of the myofilaments to Ca2+ induced by increasing SL during partial Ca2+ activation, a model was proposed that describes the tension oscillations and permits the derivation of the maximal velocity of shortening (Vmax). Vmax was increased by increasing [free Ca2+] or decreasing [free Mg2+] but not by increasing SL.
This chapter provides practical details in the use of aequorin as a biological calcium (Ca2+) indicator. The properties that make aequorin particularly suitable for this are (1) ease of signal detection, (2) high sensitivity to Ca2+, (3) relative specificity for Ca2+, and (4) lack of toxicity. Disadvantages of the photoproteins are (1) their scarcity, (2) their large molecular size, (3) the fact that they are consumed in the luminescent reaction, (4) the nonlinear relation between [Ca2+] and light intensity, (5) the influence of the chemical environment on the sensitivity to [Ca2+], and (6) the limited speed with which the luminescent reaction can follow very rapid changes in [Ca2+]. Aequorin is sufficiently difficult to obtain and to work with therefore its use should not be undertaken casually.
The Ca2+ -sensitive bioluminescent protein aequorin was microinjected into cells of frog atrial trabeculae to study intracellular calcium transients associated with excitation-contraction coupling. The amplitude of the aequorin signal increased with extracellular Ca2+ concentration and stimulus frequency, but decreased with stretch. Isoprenaline and acetylstrophanthidin both increased the amplitude, but had strikingly different effects on the time course of the signal.
1. Single twitch fibres were isolated from anterior tibial muscles of the frog, Rana pipiens. The relationship between sarcomere length and steady tetanic tension at 5 degrees C was obtained from these living fibres in the range of sarcomere lengths between about 2.2 and 1.3 microns . These fibres were then either mechanically or chemically skinned. 2. Segments were cut from the skinned fibres and mounted in an experimental chamber using a technique designed to minimize segment compliance at the points of attachment. A piece approximately 1 mm in length remained exposed to the bathing solution. 3. The segments were photographed through a light microscope at magnifications of about 460 or 110 X during activation and relaxation, so that the sarcomere lengths could be determined from a part or the whole of the segment. Activations were done with solutions of pCa either 5.49 or 6.09 and at a temperature of 5 degrees C. Fibre segments which developed striation pattern irregularities during contraction were rejected. 4. The sarcomere length-tension relation obtained from these segments in the sarcomere length range 1.3-2.2 microns was similar to that obtained from the same fibres while still living. The results were similar at the two values of pCa used. 5. These results do not support the view that sarcomere length dependent variation in the amount of calcium which is released during tetanic stimulation is a major determinant of the form of the length-tension relation in living muscle fibres at sarcomere lengths less than about 2.0 microns.
Muscle contraction is initiated by an elevation in intracellular calcium. The transient change in free calcium to a brief depolarization, the calcium transient, can be recorded using a calcium luminescent protein, aequorin. The calcium transient precedes force, peaking while force is rising and returning to the resting level as peak force is achieved. In single barnacle muscle fibers microinjected with aequorin, shortening the muscle during the declining phase of the calcium transient produces an addition light signal, indicating extra free calcium in the sarcoplasm. The amount of additional light is larger with larger length changes. It is also larger if the shortening occurs early in the calcium transient rather than later. The amount of this extra calcium correlates well with the instantaneous level of the calcium transient and not with the instantaneous force level. It is argued in a speculative manner that this extra calcium is coming from the myofilaments. This supports the hypothesis that calcium binding to the myofilaments is rapid and reversible, that reaccumulation of calcium into the sarcoplasmic reticulum (SR) could occur long before relaxation begins and that relaxation of tension could occur by some process other than the mere removal of calcium from the myofilaments.
This review is an attempt to summarize published information likely to be of value to investigators considering the use of calcium activated photoproteins such as aequorin for the detection of ionized calcium in biological systems.
In cat papillary muscles at 30 degrees C, bathed with Tyrode's solution containing 2.25 mM Ca2+, the effect of various inotropic interventions (varying the stimulus frequency and continual paired stimulation) on the shape of the steady state length-tension relation was examined at lengths from Lmax, where tension production is maximal, to 0.87 Lmax. The relative steepness of the length-tension curves for peak tension developed (DT) and for maximum rate of tension development (dT/dT) varied inversely with the degree of potentiation. Thus, during paired pulse stimulation the relative decline in DT and dT/dT for a given change in muscle length was significantly less than the decline observed during stimulation at 5 min-1. When a muscle was stretched DT did not reach its final steady level for several minutes, and this slow increase in DT contributed significantly to the steepness of the steady state length-tension relation. The half-time of the slow increase in DT exhibited beat-dependency, and conditions that reduce the transsarcolemmal influx of calcium (reduction in bathing [Ca2+] or the presence of verapamil) significantly prolonged the time course of the slow increase and reduced its magnitude. These results support the hypothesis (1) that there is length-dependence of the excitation-contraction coupling process, such that an increase in muscle length is accompanied by greater activation of the contractile system; and (2) that this is due at least in part to an increased influx of calcium into the muscle cells. The implication of this hypothesis is that the influence of muscle length on myocardial performance (the Frank-Starling relation) should not be regarded as fundamentally different in character from other inotropic interventions.
Length dependence of activation accounts almost entirely for the dependence of tension production on muscle length over the ascending limb of the length tension relation in isolated papillary muscles. If the inotropic state of the muscle is equated with the degree of activation of the contractile system, then muscle length influences inotropic state and a change of muscle length must therefore be regarded as an inotropic intervention. If these results are applicable to the intact heart, then diastolic volume and inotropic state cannot be regarded as independent regulators of cardiac output.
Tension and action potentials have been measured simultaneously from isolated cat papillary muscles. Two groups of experiments are described. In the first group, the external conditions under which the muscle contracted were changed. Specifically, stimulation rate, extra-cellular [Ca++], extracellular [Na++] were altered, and adrenaline was added to the bathing fluid. A tendency for given levels of tension to be accompanied by action potentials of constant duration is demonstrated under some of these conditions. In the second group of experiments, tension and action potentials were recorded following some change in external conditions; specifically, after a long rest, after a change in muscle length, and after the muscle had been set up in the experimental apparatus (the 'running-in' period). In the period that followed each of these interventions, peak tension increased substantially over at least several minutes but all external conditions (for example, temperature, muscle length, stimulation rate, and composition of the bathing fluid) remained constant. In each of these three situations tension increased but in one case the action potential duration increased, in another it decreased, and in the third it was unchanged. It is concluded that change in action potential durations do not necessarily make an important contribution to the changes in tension of papillary muscles.
FRANK1 and Starling2 have demonstrated that the systolic pressure developed by the heart decreased as its diastolic volume was altered in either direction from an optimum value. This law has been explained by variations of the number of cross bridges between the thin (actin) and the thick (myosin) filaments which generate force in individual cells3,4 in accordance with the sliding filament theory5.
When actin molecules form “rigor complexes” with nucleotide-free myosin, tropomn binds calcium with greater affinity and in a cooperative response the remaining actin molecules not cornplexed with myosin are “turned on” even though calcium is absent.
IT is generally agreed that the form of the length-tension relation of a fully activated skeletal muscle is determined by the overlap of actin and myosin filaments within the sarcomere. Figure 1 shows the length-tension curve for tetanised frog skeletal muscle1, which is thought to be fully activated at lengths above 75% Lmax (ref. 2). This is the form of the curve that would be expected from any muscle of similar sarcomere structure to frog muscle, provided that it has a constant degree of activation (either complete or partial) at muscle lengths above 75% Lmax. The sarcomere structure of cardiac muscle is similar to that of frog muscle3, yet the shape of its length-tension curve is strikingly different (Fig. 1). In skeletal muscle deviation from the `ideal' curve shown in Fig. 1 has been attributed to variation in the degree of activation when the muscle is stimulated at different lengths. We have investigated this possibility in cardiac muscle by studying the effect on the length-tension relation of varying the degree of activation produced by electrical stimulation: we have done this by altering the concentration of calcium in the bathing medium and by using paired pulse stimulation4.
1. The variation of isometric tetanus tension with sarcomere length in single fibres from frog striated muscle has been re‐investigated with special precautions to ensure uniformity of sarcomere length within the part of the fibre being studied.
2. In most respects the results of Ramsey & Street (1940) were confirmed, but ( a ) the peak of the curve was found to consist of a plateau between sarcomere lengths of 2·05 and 2·2 μ, ( b ) the decline of tension above this plateau is steeper than found by Ramsey & Street, and ( c ) the decline of tension below the plateau becomes suddenly steeper at a sarcomere length of about 1·67 μ.
3. Many features of this length—tension relation are simply explained on the sliding‐filament theory.
4. It is concluded that, in the plateau and at greater lengths, the tension on each thin filament is made up of equal contributions from each bridge which it overlaps on adjacent thick filaments.
5. Internal resistance to shortening is negligible in this range but becomes progressively more important with shortening below the plateau.
The effects of induced changes in muscle length on the action potential of frog ventricular strips and cat papillary muscle have been studied. When the frog preparation was stretched near the onset of contraction, the action potential duration shortened whereas a stretch during peak activity produced minimal change. Action potentials of cat papillary muscle do not alter with stretch at any time. By contrast, release of both preparations at a time when tension was near its peak, prolonged repolarisation or produced a transient depolarisation. The ECG changes corroborated the action potential changes. The release produced a deactivation of contraction which correlated with the transient depolarisation when the contraction and potential were expressed as ratios of the undisturbed measurements. Possible explanations for the results are discussed in terms of active and passive mechanisms that can relate to mechanical and electrical phenomena simultaneously. The mechanically induced transient depolarisations are clinically relevant, for regional ischaemia produces electrical and mechanical inhomogeneities which would cause contraction-excitation feedback interactions and thus electrophysiological abnormalities.
The calcium-sensitive photoprotein aequorin was microinjected into cells of rat and cat ventricular muscle. During subsequent stimulation of the muscle light emission could be detected and this signal is a function of the intracellular [Ca++]. The time course and amplitude of the intracellular [Ca++] transient occurring during contraction is described. The effects on tension and light emission of changing external [Ca++] and stimulus frequency and of adding adrenaline and caffeine to the bathing solution are described. These results show that changes in external calcium and stimulus frequency alter tension by means of changes in the intracellular [Ca++] whereas adrenaline in addition alters the sensitivity of the contractile system to intracellular [Ca++]. The results also suggest that although a fall in intracellular [Ca++] always precedes relaxation, the time course of the fall of [Ca++] is not generally a rate limiting step in the lime course of relaxation.
The authors studied the influence of inotropic factors on the shape of the relation between tension and sarcomere length. Tension measurements were performed on thin trabeculae dissected from the right ventricle of the rat heart. Sarcomere length was measured by laser diffraction techniques and controlled by a servomotor system. The relations between tension and sarcomere length were derived from contractions at various extracellular calcium concentrations [Ca 2+](o). The time course of tension development was dependent on both sarcomere length and [Ca 2+](o). At all [Ca 2+](o), the tension attained during contraction was zero at sarcomere lengths of 1.55-1.60 μm and maximal at a sarcomere length of 2.35 μm. Neither a summit nor a descending limb was found in the sarcomere length-tension relation. At [Ca 2+](o) = 0.5 mM, tension increased linearly with sarcomere length, whereas at [Ca 2+](o) = 2.5 mM, it approached maximal tension exponentially with sarcomere length. The relations between tension and sarcomere length derived from isometric contractions of the muscle and of sarcomeres were identical, and this suggests that shortening of sarcomeres does not contribute significantly to the effect of [Ca 2+]. The relations between tension and sarcomere length obtained at [Ca 2+](o) = 0.5 mM from contractions 30 sec after a potentiating burst of stimuli (4 sec at 4 Hz) were identical to the relation between tension and sarcomere length at [Ca 2+)(o) = 2.5 mM. Their results are consistent with the hypothesis that cardiac muscle length affects contractile performance by its influence on excitation contraction coupling.
The present study evaluated potential mechanisms for the slow length-dependent change in myocardial contractile state. Using 40 isolated right ventricular cat papillary muscles, we found that 10 mM caffeine reversed the subsequent slow change in myocardial performance following a change in muscle length. Since caffeine acts both at the sarcolemma and the sarcoplasmic reticulum, we attenuated the sarcolemmal influx of calcium with verapamil, manganese, and low external calcium concentration. None of these interventions altered the caffeine reversal of the length-dependent effect. It thus appears that the length-dependent alteration of contractile state is of intracellular origin, and probably related to altered calcium handling by the sarcoplasmic reticulum.
Calcium-binding proteins: relationship of binding, structure, conformation and biological function
- J D Dedman
- J R Schreiber
- W E Mandel
- R L &dmeans
POTTER, J. D., JOHNSON, J. D., DEDMAN, J. R., SCHREIBER, W. E., MANDEL, F., JACKSON, R. L.
&DMEANS, A. R. (1977). Calcium-binding proteins: relationship of binding, structure, conformation
and biological function. In Calcium binding proteins and calcium function, ed. WASSERMAN, R. H.,
CORRADINO, R. A., CARAFOLI, E., KRETSINGER, R. H., MACLENNAN, D. H. & SIEGEL, F. L., pp.
239-249. Amsterdam: Elsevier.
Caffeine reversal of length-dependent changes in myocardial contractile state in the cat. Circulation Res. 47, 592-598. 93 ) by guest on Dependence of the contractile activation of skinned cardiac cells on the sarcomere length
- L H Parmley
- W W D G Allen
- S Kurihara
- A Fabiato
- F Fabiato
CHUCK, L. H. & PARMLEY, W. W. (1980). Caffeine reversal of length-dependent changes in
myocardial contractile state in the cat. Circulation Res. 47, 592-598.
93
) by guest on July 12, 2011
jp.physoc.org
Downloaded from J Physiol (
D. G. ALLEN AND S. KURIHARA
FABIATO, A. & FABIATO, F. (1975). Dependence of the contractile activation of skinned cardiac cells
on the sarcomere length. Nature, Lond. 256, 54-56.
Co-elenterate photoproteins
- A K Campbell
- T J Lea
- C C Ashley
CAMPBELL, A. K., LEA, T. J. & ASHLEY, C. C. (1979). Co-elenterate photoproteins. In Detection and
measurement offree Call in cells, ed. ASHLEY, C. C. & CAMPBELL, A. K., pp. 13-72. Amsterdam:
Elsevier.
Factors influencing the prolongation of the active state by stretch in isolated mammalian heart
- J R Blinks
BLINKS, J. R. (1970). Factors influencing the prolongation of the active state by stretch in isolated
mammalian heart. Fedn Proc. 29, 611.
Length changes during contraction affect the intracellular [Ca2+] of heart muscle
- D G Allen
- S Kurihara
ALLEN, D. G. & KURIHARA, S. (1980b). Length changes during contraction affect the intracellular
[Ca2+] of heart muscle. J. Physiol. 310, 75-76P.