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1. Non-cross Bridge Viscoelastic Elements Contribute to Muscle Force and Work During Stretch-Shortening Cycles: Evidence From Whole Muscles and Permeabilized Fibers

   https://doi.org/10.3389/fphys.2021.648019  

   Hessel, Anthony L.; Monroy, Jenna A.; Nishikawa, Kiisa C. (March 2021, Frontiers in Physiology)

   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. 

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2. The force response of muscles to activation and length perturbations depends on length history

   https://doi.org/10.1242/jeb.243991  

   Jeong, Siwoo; Nishikawa, Kiisa (February 2023, Journal of Experimental Biology)

   ABSTRACT Recent studies have demonstrated that muscle force is not determined solely by activation under dynamic conditions, and that length history has an important role in determining dynamic muscle force. Yet, the mechanisms for how muscle force is produced under dynamic conditions remain unclear. To explore this, we investigated the effects of muscle stiffness, activation and length perturbations on muscle force. First, submaximal isometric contraction was established for whole soleus muscles. Next, the muscles were actively shortened at three velocities. During active shortening, we measured muscle stiffness at optimal muscle length (L0) and the force response to time-varying activation and length perturbations. We found that muscle stiffness increased with activation but decreased as shortening velocity increased. The slope of the relationship between maximum force and activation amplitude differed significantly among shortening velocities. Also, the intercept and slope of the relationship between length perturbation amplitude and maximum force decreased with shortening velocity. As shortening velocities were related to muscle stiffness, the results suggest that length history determines muscle stiffness and the history-dependent muscle stiffness influences the contribution of activation and length perturbations to muscle force. A two-parameter viscoelastic model including a linear spring and a linear damper in parallel with measured stiffness predicted history-dependent muscle force with high accuracy. The results and simulations support the hypothesis that muscle force under dynamic conditions can be accurately predicted as the force response of a history-dependent viscoelastic material to length perturbations. 

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3. Myosin cross-bridge kinetics slow at longer muscle lengths during isometric contractions in intact soleus from mice

   https://doi.org/10.1098/rspb.2020.2895  

   Fenwick, Axel J.; Lin, David C.; Tanner, Bertrand C. (May 2021, Proceedings of the Royal Society B: Biological Sciences)

   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. 

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4. Corn Snakes Show Consistent Sarcomere Length Ranges Across Muscle Groups and Ontogeny

   https://doi.org/10.1093/iob/obac040  

   Jurestovsky, Derek J.; Tingle, Jessica L.; Astley, Henry C. (September 2022, Integrative Organismal Biology)

   Abstract The force-generating capacity of muscle depends upon many factors including the actin-myosin filament overlap due to the relative length of the sarcomere. Consequently, the force output of a muscle may vary throughout its range of motion, and the body posture allowing maximum force generation may differ even in otherwise similar species. We hypothesized that corn snakes would show an ontogenetic shift in sarcomere length range from being centered on the plateau of the length-tension curve in small individuals to being on the descending limb in adults. Sarcomere lengths across the plateau would be advantageous for locomotion, while the descending limb would be advantageous for constriction due to the increase in force as the coil tightens around the prey. To test this hypothesis, we collected sarcomere lengths from freshly euthanized corn snakes, preserving segments in straight and maximally curved postures, and quantifying sarcomere length via light microscopy. We dissected 7 muscles (spinalis, semispinalis, multifidus, longissimus dorsi, iliocostalis (dorsal and ventral), and levator costae) in an ontogenetic series of corn snakes (mass = 80–335 g) at multiple regions along the body (anterior, middle, and posterior). Our data shows all of the muscles analyzed are on the descending limb of the length-tension curve at rest across all masses, regions, and muscles analyzed, with muscles shortening onto or past the plateau when flexed. While these results are consistent with being advantageous for constriction at all sizes, there could also be unknown benefits of this sarcomere arrangement for locomotion or striking. 

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5. Does the unusual phenomenon of sustained force circumvent the speed–endurance trade-off in the jaw muscle of the southern alligator lizard (Elgaria multicarinata)?

   https://doi.org/10.1242/jeb.247979  

   Nguyen, Allyn; Leong, Kyle; Holt, Natalie C (January 2025, Journal of Experimental Biology)

   ABSTRACT The jaw muscles of the southern alligator lizard, Elgaria multicarinata, are used in prolonged mate-holding behavior, and also to catch fast prey. In both males and females, these muscles exhibit an unusual type of high endurance known as sustained force in which contractile force does not return to baseline between subsequent contractions. This phenomenon is assumed to facilitate the prolonged mate-holding observed in this species. Skeletal muscle is often subject to a speed–endurance trade-off. Here, we determined the isometric twitch, tetanic and isotonic force–velocity properties of the jaw muscles at ∼24°C as metrics of contractile speed and compared these properties with a more typical thigh locomotory muscle to determine whether endurance by sustained force allows for circumvention of the speed–endurance trade-off. The specialized jaw muscle was generally slower than the more typical thigh muscle: time to peak twitch force, twitch 90% relaxation time (P<0.01), and tetanic 90% and 50% relaxation times (P<0.001) were significantly longer, and force–velocity properties were significantly slower (P<0.001) in the jaw than the thigh muscle. However, there seemed to be greater effects on relaxation rates and shortening velocity than on force rise times: there was no effect of muscle on time to peak, or 50% of tetanic force. Hence, the jaw muscle of the southern alligator lizard does not seem to circumvent the speed–endurance trade-off. However, the maintenance of force rise times despite slow relaxation, potentially enabled by the presence of hybrid fibers, may allow this muscle to meet the functional demand of prey capture. 

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