The length–tension curve in muscle depends on lattice spacing

Williams, C. David; Salcedo, Mary K.; Irving, Thomas C.; Regnier, Michael; Daniel, Thomas L.

doi:10.1098/rspb.2013.0697

Cited by 91 publications

(111 citation statements)

References 26 publications

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“…The reciprocal relationship between the IFS and maximal tension generation observed in this study (Table 3 and Fig. 4A) would be predicted by the theoretical work of Williams et al (23) and is in accord with the work of Colson et al, where a 1.6-nm decrease in d 1,0 due to the MLCK-induced phosphorylation of the RLC in mouse trabeculae muscles produced an ∼64% increase in maximal Ca 2+ -activated tension (24). Thus, these structural changes in the sarcomere presumably rendered defective heart performance in D166V mice and led to systolic and diastolic cardiac dysfunction ( Fig.…”

Section: Discussionsupporting

confidence: 84%

Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

Yuan

Muthu

Kazmierczak

et al. 2015

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

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127

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Myosin light chain kinase (MLCK)-dependent phosphorylation of the regulatory light chain (RLC) of cardiac myosin is known to play a beneficial role in heart disease, but the idea of a phosphorylation-mediated reversal of a hypertrophic cardiomyopathy (HCM) phenotype is novel. Our previous studies on transgenic (Tg) HCM-RLC mice revealed that the D166V (Aspartate166 →Valine) mutation-induced changes in heart morphology and function coincided with largely reduced RLC phosphorylation in situ. We hypothesized that the introduction of a constitutively phosphorylated Serine15 (S15D) into the hearts of D166V mice would prevent the development of a deleterious HCM phenotype. In support of this notion, MLCK-induced phosphorylation of D166V-mutated hearts was found to rescue some of their abnormal contractile properties. Tg-S15D-D166V mice were generated with the human cardiac RLC-S15D-D166V construct substituted for mouse cardiac RLC and were subjected to functional, structural, and morphological assessments. The results were compared with Tg-WT and Tg-D166V mice expressing the human ventricular RLC-WT or its D166V mutant, respectively. Echocardiography and invasive hemodynamic studies demonstrated significant improvements of intact heart function in S15D-D166V mice compared with D166V, with the systolic and diastolic indices reaching those monitored in WT mice. A largely reduced maximal tension and abnormally high myofilament Ca 2+ sensitivity observed in D166V-mutated hearts were reversed in S15D-D166V mice. Lowangle X-ray diffraction study revealed that altered myofilament structures present in HCM-D166V mice were mitigated in S15D-D166V rescue mice. Our collective results suggest that expression of pseudophosphorylated RLC in the hearts of HCM mice is sufficient to prevent the development of the pathological HCM phenotype.cardiomyopathy | hemodynamics | myocardial contraction | X-ray structure | myosin RLC

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Section: Discussionsupporting

confidence: 84%

Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

Yuan

Muthu

Kazmierczak

et al. 2015

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

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127

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“…Decreased relative swivelled crossbridge force decreases the FLR's ascending limb's slope in our model ( figure 5). This effect may be compensated by increasing filament lattice spacing tending to increase the slope in this range [14]. Although direct micrographic evidence is scarce [21], a range of micromechanical, biophysical and structural evidence supports the theory.…”

Section: Discussionmentioning

confidence: 92%

“…An alternative recent explanation considers two-dimensional force production of crossbridges [14]. Ignoring that myosin filaments reach the Z-disc at the point of slope change on the ascending limb (figure 2, circle), their model predicts that the increasing filament lattice spacing leads to a considerable reduction in longitudinal force, explaining the slope of the steep part of the ascending limb.…”

Section: Introductionmentioning

confidence: 99%

Myosin filament sliding through the Z-disc relates striated muscle fibre structure to function

et al. 2016

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Striated muscle contraction requires intricate interactions of microstructures. The classic textbook assumption that myosin filaments are compressed at the meshed Z-disc during striated muscle fibre contraction conflicts with experimental evidence. For example, myosin filaments are too stiff to be compressed sufficiently by the muscular force, and, unlike compressed springs, the muscle fibres do not restore their resting length after contractions to short lengths. Further, the dependence of a fibre's maximum contraction velocity on sarcomere length is unexplained to date. In this paper, we present a structurally consistent model of sarcomere contraction that reconciles these findings with the well-accepted sliding filament and crossbridge theories. The few required model parameters are taken from the literature or obtained from reasoning based on structural arguments. In our model, the transition from hexagonal to tetragonal actin filament arrangement near the Z-disc together with a thoughtful titin arrangement enables myosin filament sliding through the Z-disc. This sliding leads to swivelled crossbridges in the adjacent half-sarcomere that dampen contraction. With no fitting of parameters required, the model predicts straightforwardly the fibre's entire force-length behaviour and the dependence of the maximum contraction velocity on sarcomere length. Our model enables a structurally and functionally consistent view of the contractile machinery of the striated fibre with possible implications for muscle diseases and evolution. BackgroundAs motors of life, muscles convert chemical energy into mechanical energy and heat. Muscles transport substances within the body, stabilize the skeleton and enable locomotion. The first property characterizing the mechanical function of striated muscles to be described [1] was the active isometric force-length relationship (FLR). This property shows the maximal forces the striated muscle fibre can produce by electrical stimulation at different constant lengths. The classic FLR (figure 1, straight lines) [2] with its strikingly linear segments has been described not only up to the fibre level but also for the whole muscle [7,8]. Despite the fact that this relationship represents basic textbook knowledge for life science students, to date a convincing structural model explaining the shape of the entire FLR does not exist.According to the sliding filament [4,5] and crossbridge [6] theories, actin and myosin filaments slide relative to each other in response to forces generated by temporary crossbridges formed by myosin heads-projecting from the myosin filaments-and actin filaments. This yields straightforward geometric explanations for the plateau region and for the region of decreasing isometric force based on filament lengths ( figure 1, black lines) [2]. The slope change (figure 1, black circle) in the range of increasing isometric force (ascending limb) is typically related to myosin filaments hitting the Z-disc, a thinmeshed filament structure [9] defining the sarcomere bounda...

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“…7A differs from that expected on the overlap between myofilaments (which is maximum at about 2.6 µm), because tension is measured on tetanus rise (3 ms after the stimulus). Compared with the tetanus plateau, the force development measured during tetanus rise is modulated both by myofilament overlap and by changes to myofibrillar calcium sensitivity with sarcomere length (Williams et al, 2013). To test for any interaction between crossbridges and static stiffness, the above-mentioned relationships were further studied by adding BTS, a crossbridge inhibitor that reduces active tension without affecting calcium release, to the normal solution (Pinniger et al, 2006).…”

Section: Static Stiffness Dependence On Sarcomere Lengthmentioning

confidence: 99%

Non-crossbridge stiffness in active muscle fibres

Colombini

Nocella

Bagni

2016

Journal of Experimental Biology

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Stretching of an activated skeletal muscle induces a transient tension increase followed by a period during which the tension remains elevated well above the isometric level at an almost constant value. This excess of tension in response to stretching has been called 'static tension' and attributed to an increase in fibre stiffness above the resting value, named 'static stiffness'. This observation was originally made, by our group, in frog intact muscle fibres and has been confirmed more recently, by us, in mammalian intact fibres. Following stimulation, fibre stiffness starts to increase during the latent period well before crossbridge force generation and it is present throughout the whole contraction in both single twitches and tetani. Static stiffness is dependent on sarcomere length in a different way from crossbridge force and is independent of stretching amplitude and velocity. Static stiffness follows a time course which is distinct from that of active force and very similar to the myoplasmic calcium concentration time course. We therefore hypothesize that static stiffness is due to a calcium-dependent stiffening of a noncrossbridge sarcomere structure, such as the titin filament. According to this hypothesis, titin, in addition to its well-recognized role in determining the muscle passive tension, could have a role during muscle activity.

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The length–tension curve in muscle depends on lattice spacing

Cited by 91 publications

References 26 publications

Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice

Myosin filament sliding through the Z-disc relates striated muscle fibre structure to function

Non-crossbridge stiffness in active muscle fibres

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