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Actomyosin based contraction: one mechanokinetic model from single molecules to muscle?

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ABSTRACT

Bridging the gaps between experimental systems on different hierarchical scales is needed to overcome remaining challenges in the understanding of muscle contraction. Here, a mathematical model with well-characterized structural and biochemical actomyosin states is developed to that end. We hypothesize that this model accounts for generation of force and motion from single motor molecules to the large ensembles of muscle. In partial support of this idea, a wide range of contractile phenomena are reproduced without the need to invoke cooperative interactions or ad hoc states/transitions. However, remaining limitations exist, associated with ambiguities in available data for model definition e.g.: (1) the affinity of weakly bound cross-bridges, (2) the characteristics of the cross-bridge elasticity and (3) the exact mechanistic relationship between the force-generating transition and phosphate release in the actomyosin ATPase. Further, the simulated number of attached myosin heads in the in vitro motility assay differs several-fold from duty ratios, (fraction of strongly attached ATPase cycle times) derived in standard analysis. After addressing the mentioned issues the model should be useful in fundamental studies, for engineering of myosin motors as well as for studies of muscle disease and drug development.

Electronic supplementary material: The online version of this article (doi:10.1007/s10974-016-9458-0) contains supplementary material, which is available to authorized users.

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Plots of displacement (left vertical axis; full line) and number of attached myosin heads (right axis; dashed line) against time for filaments propelled by low number of myosin motors. a 0.20 µm long filament. Note, temporary stops in motility interspersed with phases of rapid displacement. b One example of simulation assuming 0.15 µm long filament. c Second example of 0.15 µm long filament. Note, switch in position upon myosin head attachment but no net displacement. Assumed motor density, 1000 µm−2 (see “Materials and Methods” section, text under Eq. 1) corresponding to 4–5 and 6 myosin heads available for interaction with 0.15 and 0.20 µm long filaments, respectively
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Fig4: Plots of displacement (left vertical axis; full line) and number of attached myosin heads (right axis; dashed line) against time for filaments propelled by low number of myosin motors. a 0.20 µm long filament. Note, temporary stops in motility interspersed with phases of rapid displacement. b One example of simulation assuming 0.15 µm long filament. c Second example of 0.15 µm long filament. Note, switch in position upon myosin head attachment but no net displacement. Assumed motor density, 1000 µm−2 (see “Materials and Methods” section, text under Eq. 1) corresponding to 4–5 and 6 myosin heads available for interaction with 0.15 and 0.20 µm long filaments, respectively

Mentions: Key results for short actin filaments and low myosin surface densities are also predicted (Fig. 4) such as the tendency for stops and pauses in motility, intervened by periods of rapid sliding when the number of available myosin heads is reduced below a certain critical value (Hilbert et al. 2013). Furthermore, in accordance with a minimum actin filament length of ~0.15 µm for maintained sliding at a myosin head density of 1000 µm−2 (Toyoshima et al. 1990), extended periods without attached myosin heads and/or without filament sliding (Fig. 4c), were observed in simulations under these assumptions.Fig. 4


Actomyosin based contraction: one mechanokinetic model from single molecules to muscle?
Plots of displacement (left vertical axis; full line) and number of attached myosin heads (right axis; dashed line) against time for filaments propelled by low number of myosin motors. a 0.20 µm long filament. Note, temporary stops in motility interspersed with phases of rapid displacement. b One example of simulation assuming 0.15 µm long filament. c Second example of 0.15 µm long filament. Note, switch in position upon myosin head attachment but no net displacement. Assumed motor density, 1000 µm−2 (see “Materials and Methods” section, text under Eq. 1) corresponding to 4–5 and 6 myosin heads available for interaction with 0.15 and 0.20 µm long filaments, respectively
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5383694&req=5

Fig4: Plots of displacement (left vertical axis; full line) and number of attached myosin heads (right axis; dashed line) against time for filaments propelled by low number of myosin motors. a 0.20 µm long filament. Note, temporary stops in motility interspersed with phases of rapid displacement. b One example of simulation assuming 0.15 µm long filament. c Second example of 0.15 µm long filament. Note, switch in position upon myosin head attachment but no net displacement. Assumed motor density, 1000 µm−2 (see “Materials and Methods” section, text under Eq. 1) corresponding to 4–5 and 6 myosin heads available for interaction with 0.15 and 0.20 µm long filaments, respectively
Mentions: Key results for short actin filaments and low myosin surface densities are also predicted (Fig. 4) such as the tendency for stops and pauses in motility, intervened by periods of rapid sliding when the number of available myosin heads is reduced below a certain critical value (Hilbert et al. 2013). Furthermore, in accordance with a minimum actin filament length of ~0.15 µm for maintained sliding at a myosin head density of 1000 µm−2 (Toyoshima et al. 1990), extended periods without attached myosin heads and/or without filament sliding (Fig. 4c), were observed in simulations under these assumptions.Fig. 4

View Article: PubMed Central - PubMed

ABSTRACT

Bridging the gaps between experimental systems on different hierarchical scales is needed to overcome remaining challenges in the understanding of muscle contraction. Here, a mathematical model with well-characterized structural and biochemical actomyosin states is developed to that end. We hypothesize that this model accounts for generation of force and motion from single motor molecules to the large ensembles of muscle. In partial support of this idea, a wide range of contractile phenomena are reproduced without the need to invoke cooperative interactions or ad hoc states/transitions. However, remaining limitations exist, associated with ambiguities in available data for model definition e.g.: (1) the affinity of weakly bound cross-bridges, (2) the characteristics of the cross-bridge elasticity and (3) the exact mechanistic relationship between the force-generating transition and phosphate release in the actomyosin ATPase. Further, the simulated number of attached myosin heads in the in vitro motility assay differs several-fold from duty ratios, (fraction of strongly attached ATPase cycle times) derived in standard analysis. After addressing the mentioned issues the model should be useful in fundamental studies, for engineering of myosin motors as well as for studies of muscle disease and drug development.

Electronic supplementary material: The online version of this article (doi:10.1007/s10974-016-9458-0) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus