ABSTRACT Residual force enhancement (RFE) is the increase in steady-state force after active stretch relative to the force during isometric contraction at the same final length. The muscular dystrophy with myositis (mdm) mutation in mice, characterized by a small deletion in N2A titin, has been proposed to prevent N2A titin–actin interactions so that active mdm muscles are more compliant than wild type (WT). This decrease in active muscle stiffness is associated with reduced RFE. We investigated RFE in permeabilized soleus (SOL) and extensor digitorum longus (EDL) fiber bundles from WT and mdm mice. On each fiber bundle, we performed active and passive stretches from an average sarcomere length of 2.6–3.0 µm at a slow rate of 0.04 µm s−1, as well as isometric contractions at the initial and final lengths. One-way ANOVA showed that SOL and EDL fiber bundles from mdm mice exhibited significantly lower RFE than WT mice (P<0.0001). This result is consistent with previous observations in single myofibrils and intact muscles. However, it contradicts the results from a previous study that appeared to show that compensatory mechanisms could restore titin force enhancement in single fibers from mdm psoas. We suggest that RFE measured previously in mdm single fibers was an artifact of the high variability in passive tension found in degenerating fibers, which begins after ∼24 days of age. The results are consistent with the hypothesis that RFE is reduced in mdm skeletal muscles owing to impaired Ca2+-dependent titin–actin interactions resulting from the small deletion in N2A titin.
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Effects of shortening velocity on the stiffness to force ratio during isometric force redevelopment suggest mechanisms of residual force depression
Although the phenomenon of residual force depression has been known for decades, the mechanisms remain elusive. In the present study, we investigated mechanisms of residual force depression by measuring the stiffness to force ratio during force redevelopment after shortening at different velocities. The results showed that the slope of the relationship between muscle stiffness and force decreased with decreasing shortening velocity, and the y-intercept increased with decreasing shortening velocity. The differing slopes and y-intercepts indicate that the stiffness to force ratio during isometric force redevelopment depends on the active shortening velocity at a given muscle length and activation level. The greater stiffness to force ratio after active shortening can potentially be explained by weakly-bound cross bridges in the new overlap zone. However, weakly-bound cross bridges are insufficient to explain the reduced slope at the slowest shortening velocity because the reduced velocity should increase the proportion of weakly- to strongly-bound cross bridges, thereby increasing the slope. In addition, if actin distortion caused by active shortening recovers during the force redevelopment period, then the resulting slope should be similar to the non-linear slope of force redevelopment over time. Alternatively, we suggest that a tunable elastic element, such as titin, could potentially explain the results.
more » « less- Award ID(s):
- 2016054
- NSF-PAR ID:
- 10391773
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 13
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Key points Maximum fascicle shortening/rotation was significantly decreased in paretic medial gastrocnemius (MG) muscles compared to non‐paretic MG muscles.
The fascicle gear ratio on both sides decreased as the ankle became dorsiflexed, but the slope of the fascicle gear ratio over ankle joint angle was significantly lower on the paretic side.
The side‐to‐side slope difference was strongly correlated with the relative maximum joint torque and with the relative shear wave speed, suggesting that variable gearing may explain muscle weakness after stroke.
Abstract The present study aimed to understand variable fascicle gearing during voluntary isometric contractions of the medial gastrocnemius (MG) muscle in chronic stroke survivors. Using ultrasonography, we characterized fascicle behaviour on both paretic and non‐paretic sides during plantarflexion contractions at different intensities and at different ankle joint angles. Shear wave speed was also recorded from the MG muscle belly under passive conditions. Fascicle gear ratios were then calculated as the ratio of muscle belly shortening velocity to fascicle shortening velocity, and variable fascicle gearing was quantified from the slope of gear ratio
vs . joint angle relations. This slope was used to establish associations with maximum joint torques and with shear wave speeds. At all measured angles, we found a significant reduction in both maximum fascicle shortening and maximum fascicle rotation on the paretic side compared to the non‐paretic side on our stroke survivor cohort. The fascicle rotation per fascicle shortening on the paretic side was also significantly smaller than on the non‐paretic side, especially at plantarflexed positions. Furthermore, the fascicle gear ratio on both sides decreased as the ankle became dorsiflexed, but the change in the fascicle gear ratio was significantly lower on the paretic side. The side‐to‐side difference in the gear ratio slope was also strongly correlated with the relative maximum joint torque and with the relative shear wave speed, suggesting that variable gearing may explain muscle weakness after stroke. Further studies are needed to investigate how muscular changes after stroke may impede variable gearing and adversely impact muscle performance. -
null (Ed.)The sliding filament–swinging cross bridge theory of skeletal muscle contraction provides a reasonable description of muscle properties during isometric contractions at or near maximum isometric force. However, it fails to predict muscle force during dynamic length changes, implying that the model is not complete. Mounting evidence suggests that, along with cross bridges, a Ca 2+ -sensitive viscoelastic element, likely the titin protein, contributes to muscle force and work. The purpose of this study was to develop a multi-level approach deploying stretch-shortening cycles (SSCs) to test the hypothesis that, along with cross bridges, Ca 2+ -sensitive viscoelastic elements in sarcomeres contribute to force and work. Using whole soleus muscles from wild type and mdm mice, which carry a small deletion in the N2A region of titin, we measured the activation- and phase-dependence of enhanced force and work during SSCs with and without doublet stimuli. In wild type muscles, a doublet stimulus led to an increase in peak force and work per cycle, with the largest effects occurring for stimulation during the lengthening phase of SSCs. In contrast, mdm muscles showed neither doublet potentiation features, nor phase-dependence of activation. To further distinguish the contributions of cross bridge and non-cross bridge elements, we performed SSCs on permeabilized psoas fiber bundles activated to different levels using either [Ca 2+ ] or [Ca 2+ ] plus the myosin inhibitor 2,3-butanedione monoxime (BDM). Across activation levels ranging from 15 to 100% of maximum isometric force, peak force, and work per cycle were enhanced for fibers in [Ca 2+ ] plus BDM compared to [Ca 2+ ] alone at a corresponding activation level, suggesting a contribution from Ca 2+ -sensitive, non-cross bridge, viscoelastic elements. Taken together, our results suggest that a tunable viscoelastic element such as titin contributes to: (1) persistence of force at low [Ca 2+ ] in doublet potentiation; (2) phase- and length-dependence of doublet potentiation observed in wild type muscles and the absence of these effects in mdm muscles; and (3) increased peak force and work per cycle in SSCs. We conclude that non-cross bridge viscoelastic elements, likely titin, contribute substantially to muscle force and work, as well as the phase-dependence of these quantities, during dynamic length changes.more » « less
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null (Ed.)Muscle contraction results from force-generating cross-bridge interactions between myosin and actin. Cross-bridge cycling kinetics underlie fundamental contractile properties, such as active force production and energy utilization. Factors that influence cross-bridge kinetics at the molecular level propagate through the sarcomeres, cells and tissue to modulate whole-muscle function. Conversely, movement and changes in the muscle length can influence cross-bridge kinetics on the molecular level. Reduced, single-molecule and single-fibre experiments have shown that increasing the strain on cross-bridges may slow their cycling rate and prolong their attachment duration. However, whether these strain-dependent cycling mechanisms persist in the intact muscle tissue, which encompasses more complex organization and passive elements, remains unclear. To investigate this multi-scale relationship, we adapted traditional step-stretch protocols for use with mouse soleus muscle during isometric tetanic contractions, enabling novel estimates of length-dependent cross-bridge kinetics in the intact skeletal muscle. Compared to rates at the optimal muscle length ( L o ), we found that cross-bridge detachment rates increased by approximately 20% at 90% of L o (shorter) and decreased by approximately 20% at 110% of L o (longer). These data indicate that cross-bridge kinetics vary with whole-muscle length during intact, isometric contraction, which could intrinsically modulate force generation and energetics, and suggests a multi-scale feedback pathway between whole-muscle function and cross-bridge activity.more » « less
