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1. Cardiac myosin binding protein-C phosphorylation accelerates β-cardiac myosin detachment rate in mouse myocardium

   https://doi.org/10.1152/ajpheart.00673.2020  

   Tanner, Bertrand C. ; Previs, Michael J. ; Wang, Yuan ; Robbins, Jeffrey ; Palmer, Bradley M. ( May 2021 , American Journal of Physiology-Heart and Circulatory Physiology)

   null (Ed.)

   Cardiac myosin binding protein-C (cMyBP-C) is a thick filament protein that influences sarcomere stiffness and modulates cardiac contraction-relaxation through its phosphorylation. Phosphorylation of cMyBP-C and ablation of cMyBP-C have been shown to increase the rate of MgADP release in the acto-myosin cross-bridge cycle in the intact sarcomere. The influence of cMyBP-C on Pi-dependent myosin kinetics has not yet been examined. We investigated the effect of cMyBP-C, and its phosphorylation, on myosin kinetics in demembranated papillary muscle strips bearing the β-cardiac myosin isoform from nontransgenic and homozygous transgenic mice lacking cMyBP-C. We used quick stretch and stochastic length-perturbation analysis to characterize rates of myosin detachment and force development over 0–12 mM Pi and at maximal (pCa 4.8) and near-half maximal (pCa 5.75) Ca 2+ activation. Protein kinase A (PKA) treatment was applied to half the strips to probe the effect of cMyBP-C phosphorylation on Pi sensitivity of myosin kinetics. Increasing Pi increased myosin cross-bridge detachment rate similarly for muscles with and without cMyBP-C, although these rates were higher in muscle without cMyBP-C. Treating myocardial strips with PKA accelerated detachment rate when cMyBP-C was present over all Pi, but not when cMyBP-C was absent. The rate of force development increased with Pi in all muscles. However, Pi sensitivity of the rate force development was reduced when cMyBP-C was present versus absent, suggesting that cMyBP-C inhibits Pi-dependent reversal of the power stroke or stabilizes cross-bridge attachment to enhance the probability of completing the power stroke. These results support a functional role for cMyBP-C in slowing myosin detachment rate, possibly through a direct interaction with myosin or by altering strain-dependent myosin detachment via cMyBP-C-dependent stiffness of the thick filament and myofilament lattice. PKA treatment reduces the role for cMyBP-C to slow myosin detachment and thus effectively accelerates β-myosin detachment in the intact myofilament lattice. NEW & NOTEWORTHY Length perturbation analysis was used to demonstrate that β-cardiac myosin characteristic rates of detachment and recruitment in the intact myofilament lattice are accelerated by Pi, phosphorylation of cMyBP-C, and the absence of cMyBP-C. The results suggest that cMyBP-C normally slows myosin detachment, including Pi-dependent detachment, and that this inhibition is released with phosphorylation or absence of cMyBP-C. 

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2. Muscle as a tunable material: implications for achieving muscle-like function in robotic prosthetic devices

   https://doi.org/10.1242/jeb.225086  

   Nishikawa, Kiisa ; Huck, Thomas G. ( October 2021 , Journal of Experimental Biology)

   ABSTRACT An ideal prosthesis should perform as well as or better than the missing limb it was designed to replace. Although this ideal is currently unattainable, recent advances in design have significantly improved the function of prosthetic devices. For the lower extremity, both passive prostheses (which provide no added power) and active prostheses (which add propulsive power) aim to emulate the dynamic function of the ankle joint, whose adaptive, time-varying resistance to applied forces is essential for walking and running. Passive prostheses fail to normalize energetics because they lack variable ankle impedance that is actively controlled within each gait cycle. By contrast, robotic prostheses can normalize energetics for some users under some conditions. However, the problem of adaptive and versatile control remains a significant issue. Current prosthesis-control algorithms fail to adapt to changes in gait required for walking on level ground at different speeds or on ramps and stairs. A new paradigm of ‘muscle as a tunable material’ versus ‘muscle as a motor’ offers insights into the adaptability and versatility of biological muscles, which may provide inspiration for prosthesis design and control. In this new paradigm, neural activation tunes muscle stiffness and damping, adapting the response to applied forces rather than instructing the timing and amplitude of muscle force. A mechanistic understanding of muscle function is incomplete and would benefit from collaboration between biologists and engineers. An improved understanding of the adaptability of muscle may yield better models as well as inspiration for developing prostheses that equal or surpass the functional capabilities of biological limbs across a wide range of conditions. 

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3. Monitoring muscle over three orders of magnitude: Widespread positive allometry among locomotor and body support musculature in the pectoral girdle of varanid lizards ( Varanidae )

   https://doi.org/10.1111/joa.13273  

   Cieri, Robert L. ; Dick, Taylor J. M. ; Clemente, Christofer J. ( July 2020 , Journal of Anatomy)

   There is a functional trade‐off in the design of skeletal muscle. Muscle strength depends on the number of muscle fibers in parallel, while shortening velocity and operational distance depend on fascicle length, leading to a trade‐off between the maximum force a muscle can produce and its ability to change length and contract rapidly. This trade‐off becomes even more pronounced as animals increase in size because muscle strength scales with area (length²) while body mass scales with volume (length³). In order to understand this muscle trade‐off and how animals deal with the biomechanical consequences of size, we investigated muscle properties in the pectoral girdle of varanid lizards. Varanids are an ideal group to study the scaling of muscle properties because they retain similar body proportions and posture across five orders of magnitude in body mass and are highly active, terrestrially adapted reptiles. We measured muscle mass, physiological cross‐sectional area, fascicle length, proximal and distal tendon lengths, and proximal and distal moment arms for 27 pectoral girdle muscles in 13 individuals across 8 species ranging from 64 g to 40 kg. Standard and phylogenetically informed reduced major axis regression was used to investigate how muscle architecture properties scale with body size. Allometric growth was widespread for muscle mass (scaling exponent >1), physiological cross‐sectional area (scaling exponent >0.66), but not tendon length (scaling exponent >0.33). Positive allometry for muscle mass was universal among muscles responsible for translating the trunk forward and flexing the elbow, and nearly universal among humeral protractors and wrist flexors. Positive allometry for PCSA was also common among trunk translators and humeral protractors, though less so than muscle mass. Positive scaling for fascicle length was not widespread, but common among humeral protractors. A higher proportion of pectoral girdle muscles scaled with positive allometry than our previous work showed for the pelvic girdle, suggesting that the center of mass may move cranially with body size in varanids, or that the pectoral girdle may assume a more dominant role in locomotion in larger species. Scaling exponents for physiological cross‐sectional area among muscles primarily associated with propulsion or with a dual role were generally higher than those associated primarily with support against gravity, suggesting that locomotor demands have at least an equal influence on muscle architecture as body support. Overall, these results suggest that larger varanids compensate for the increased biomechanical demands of locomotion and body support at higher body sizes by developing larger pectoral muscles with higher physiological cross‐sectional areas. The isometric scaling rates for fascicle length among locomotion‐oriented pectoral girdle muscles suggest that larger varanids may be forced to use shorter stride lengths, but this problem may be circumvented by increases in limb excursion afforded by the sliding coracosternal joint.

    

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4. Some Challenges of Playing with Power: Does Complex Energy Flow Constrain Neuromuscular Performance?

   https://doi.org/10.1093/icb/icz108  

   Roberts, Thomas J. ( June 2019 , Integrative and Comparative Biology)

   Many studies of the flow of energy between the body, muscles, and elastic elements highlight advantages of the storage and recovery of elastic energy. The spring-like action of structures associated with muscles allows for movements that are less costly, more powerful and safer than would be possible with contractile elements alone. But these actions also present challenges that might not be present if the pattern of energy flow were simpler, for example, if power were always applied directly from muscle to motions of the body. Muscle is under the direct control of the nervous system, and precise modulation of activity can allow for finely controlled displacement and force. Elastic structures deform under load in a predictable way, but are not under direct control, thus both displacement and the flow of energy act at the mercy of the mechanical interaction of muscle and forces associated with movement. Studies on isolated muscle-tendon units highlight the challenges of controlling such systems. A carefully tuned activation pattern is necessary for effective cycling of energy between tendon and the environment; most activation patterns lead to futile cycling of energy between tendon and muscle. In power-amplified systems, “elastic backfire” sometimes occurs, where energy loaded into tendon acts to lengthen active muscles, rather than accelerate the body. Classic models of proprioception that rely on muscle spindle organs for sensing muscle and joint displacement illustrate how elastic structures might influence sensory feedback by decoupling joint movement from muscle fiber displacements. The significance of the complex flow of energy between muscles, elastic elements and the body for neuromotor control is worth exploring.

    

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5. 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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