The stretch-shortening cycle effect is prominent in the inhibited force state
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Stretch shortening cycle
Cardiac muscle
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Muscle fibre
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Myofilament
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We studied sarcomere performance in single isolated intact frog atrial cells using techniques that allow direct measurement of sarcomere length and force. The purpose of this investigation was to determine whether length-dependent alterations in contractile activation occur in the single isolated cardiac cell. This was accomplished by determining the effect of initial sarcomere length on the time course of sarcomere shortening and force development during auxotonic twitch contractions. The results presented in this paper demonstrate that the velocity of sarcomere shortening, the rate of force development, and the magnitude of force development during auxotonic twitch contractions all increase as initial sarcomere length increases over the range of about 2 micrometers to greater than 3 micrometers. These results indicate that the level of contractile activation increases as initial sarcomere length increases. Also, results are presented that indicate that the rate of increase of contractile activation during a twitch contraction also increases as initial sarcomere length increases. These length-dependent effects on contractile activation in conjunction with the slow time course of contractile activation cause the force-velocity-length relationship to be time-dependent: i.e., the velocity of sarcomere shortening at a given sarcomere length and load depends on the time during the contraction when the sarcomere reaches that length. The results suggest that length-dependent alterations in contractile activation may play a major role in the improved contractile performance that accompanies an increase in initial sarcomere length in cardiac muscle.
Cardiac muscle
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The functional unit of muscle is the half-sarcomere in which crossbridges attach and cycle between interdigitating arrays of thick and thin filaments. Half-sarcomeres shorten during contraction if the force produced by the crossbridges is greater than the external force and are stretched if the force produced by the crossbridges is less than the external force. A typical muscle cell will have many thousands of half-sarcomeres in series so the overall performance of a muscle can be a complex function of the behaviour of individual half-sarcomeres. However, until recently, only whole sarcomere lengths could be measured except in electron micrographs. Sarcomere uniformity has long been a topic of interest and it is known, for instance, that in isolated single fibres the sarcomere lengths tend to be longer near the end of the fibre than at the middle. For this reason, Gordon et al. (1966) in their classic study of the force–length relation of single fibres, developed the length clamp and applied it to a middle region of the fibre where the sarcomere uniformity was greatest. It is also recognized that sarcomere non-uniformity can occur in intact muscles, particularly after they are stretched during contraction, often known as eccentric contractions. Thus, Fridén et al. 1981) persuaded men to run down 100 flights of stairs. This resulted in severe pain in the stretched muscle groups in the following 2–3 days and muscle biopsies showed regions of disrupted sarcomeres in which overstretched and understretched sarcomeres could be observed. Sarcomeres are particularly likely to be unstable at long sarcomere lengths (SLs). In mammalian muscles the plateau of the force–length curve lies between SLs 2.0 and 2.4 μm and force falls at longer SLs reaching zero at 3.9 μm (Edman, 2005). Imagine two sarcomeres in series with SLs > 2.4 μm. If one is slightly weaker, then it will tend to be stretched by its stronger neighbour; but the stretching makes it weaker still. This cycle will tend to lead to increasing variability of SLs on the descending limb but not on the ascending limb or the plateau. This potential instability on the descending limb is minimized by various factors, particularly the passive elasticity provided by titin and the fact that the force–velocity curve has a different slope for stretching rather than shortening. These ideas were greatly expanded by Morgan (1990) who pointed out that the force–velocity relation allows very high velocities once the stretching force exceeds about 1.6 × isometric force. Consequently when muscle are stretched moderately rapidly on the descending limb it is possible for the weakest sarcomeres to stretch very rapidly until stabilized at long (non-overlap, > 3.9 μm) sarcomere lengths by the passive force provided by titin and other cytoskeletal proteins. This ‘popping sarcomere’ theory has provided many insights in the behaviour of muscles when stretched during contraction (for recent review see Proske & Morgan, 2001). A new study in this issue of The Journal of Physiology by Telley et al. (2006) makes an important contribution to this story. In a technical tour de force this group has attached fluorescent antibodies to α-actinin in the Z-line and myomesin in the M-band (the centre of the thick filaments). Thus the length of individual half-sarcomeres could be detected rather than the whole sarcomeres. This is potentially important because the two half-sarcomeres of a sarcomere do not necessarily perform in parallel. The preparation used by Telley et al. (2006) was a single (skinned) myofibril of rabbit skeletal muscle which can be rapidly activated and relaxed by appropriate solution changes. From images of the preparation, which contained 20–60 half-sarcomeres, the length of each half-sarcomere can be determined during development of force, during stretch and during the subsequent relaxation. The behaviour of half-sarcomeres turns out to be complex. For instance during contraction some half-sarcomeres shorten while others extend. Less easily understood is that half-sarcomeres that stretched during isometric contraction (weak half-sarcomeres) were not necessarily the ones that show the greatest increase in length during the subsequent stretch. In addition, pairs of half-sarcomeres were observed in which one was short and the neighbour was long (asymmetric sarcomeres). A key point, however, is that no overextended sarcomeres (popped sarcomeres; SL > 3.9 μm) were observed despite conditions which might be expected to trigger popping. Do these observations invalidate the ‘popping sarcomere’ theory? Not yet. Firstly, the SLs used were only just into the descending limb. Secondly, in a myofibrillar preparation most of the desmin will be lost. The authors argue that this should make the preparation more susceptible to sarcomere popping but in some knock-out studies, muscles lacking desmin appear to be resistant to stretch-induced damage (Sam et al. 2000). Thirdly, in the EM study of Brown & Hill (1991) stretched muscles showed over- and under-stretch sarcomeres in myofilaments within a single myofibril, so it is possible that the averaging across a single myofibril disguises some of the heterogeneity of sarcomere lengths. Nevertheless, the approach used by Telley et al. (2006) represents an important step forward for understanding sarcomere properties, and the ability to observe every half-sarcomere in a functioning myofibril will undoubtedly bring new insights into the complexities of muscle contraction.
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The sarcomere pattern and tension of atrial trabeculae isolated from frog hearts have been monitored. The sarcomere length at zero tension varied with the size of the trabeculae but was never less than 1.88 pm, at which length the ends of the thin filaments are at the centre of the A band. Resting tension became large at sarcomere lengths greater than 2.3 m̈m. It was difficult to stretch the trabeculae to produce sarcomere lengths greater than 2.7 m̈m and doing so generally resulted in irreversible changes. Sarcomeres as long as 3.2 m̈m were seen, however, in cells in series with spontaneously contracting fibres. Broadening of the A band at larger sarcomere lengths was interpreted as indicating misalignment of thick filaments and suggests that thick and thin filaments interact in the resting heart. The entire change in length of the central undamaged half of the trabeculae during stretching could be accounted for by the change in sarcomere length.
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In cardiac muscle, contraction is triggered by sarcolemmal depolarization, resulting in an intracellular Ca2+ transient, binding of Ca2+ to troponin, and subsequent cross-bridge formation (excitation–contraction [EC] coupling). Here, we develop a novel experimental system for simultaneous nano-imaging of intracellular Ca2+ dynamics and single sarcomere length (SL) in rat neonatal cardiomyocytes. We achieve this by expressing a fluorescence resonance energy transfer (FRET)–based Ca2+ sensor yellow Cameleon–Nano (YC-Nano) fused to α-actinin in order to localize to the Z disks. We find that, among four different YC-Nanos, α-actinin–YC-Nano140 is best suited for high-precision analysis of EC coupling and α-actinin–YC-Nano140 enables quantitative analyses of intracellular calcium transients and sarcomere dynamics at low and high temperatures, during spontaneous beating and with electrical stimulation. We use this tool to show that calcium transients are synchronized along the length of a myofibril. However, the averaging of SL along myofibrils causes a marked underestimate (∼50%) of the magnitude of displacement because of the different timing of individual SL changes, regardless of the absence or presence of positive inotropy (via β-adrenergic stimulation or enhanced actomyosin interaction). Finally, we find that β-adrenergic stimulation with 50 nM isoproterenol accelerated Ca2+ dynamics, in association with an approximately twofold increase in sarcomere lengthening velocity. We conclude that our experimental system has a broad range of potential applications for the unveiling molecular mechanisms of EC coupling in cardiomyocytes at the single sarcomere level.
Myofibril
Calcium in biology
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Troponin C
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We examined length changes of individual half-sarcomeres during and after stretch in actively contracting, single rabbit psoas myofibrils containing 10-30 sarcomeres. The myofibrils were fluorescently immunostained so that both Z-lines and M-bands of sarcomeres could be monitored by video microscopy simultaneously with the force measurement. Half-sarcomere lengths were determined by processing of video images and tracking the fluorescent Z-line and M-band signals. Upon Ca2+ activation, during the rise in force, active half-sarcomeres predominantly shorten but to different extents so that an active myofibril consists of half-sarcomeres of different lengths and thus asymmetric sarcomeres, i.e. shifted A-bands, indicating different amounts of filament overlap in the two halves. When force reached a plateau, the myofibril was stretched by 15-20% resting length (L0) at a velocity of approximately 0.2 L0 s(-1). The myofibril force response to a ramp stretch is similar to that reported from muscle fibres. Despite the approximately 2.5-fold increase in force due to the stretch, the variability in half-sarcomere length remained almost constant during the stretch and A-band shifts did not progress further, independent of whether half-sarcomeres shortened or lengthened during the initial Ca2+ activation. Moreover, albeit half-sarcomeres lengthened to different extents during a stretch, rapid elongation of individual sarcomeres beyond filament overlap ('popping') was not observed. Thus, in contrast to predictions of the 'popping sarcomere' hypothesis, a stretch rather stabilizes the uniformity of half-sarcomere lengths and sarcomere symmetry. In general, the half-sarcomere length changes (dynamics) before and after stretch were slow and the dynamics after stretch were not readily predictable on the basis of the steady-state force-sarcomere length relation.
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