The spatial distribution of thin filament activation influences force development and myosin activity in computational models of muscle contraction
The spatial distribution of thin filament activation influences force development and myosin activity in computational models of muscle contraction
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DOI：
10.1016/j.abb.2021.108855
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发表时间：
2021-03-31
影响因子：
3.9
通讯作者：
Tanner, Bertrand C. W.
中科院分区：
文献类型：
--
作者：
Fenwick, Axel J.;Wood, Alexander M.;Tanner, Bertrand C. W.
横纹肌收缩是由Ca 2+结合并激活肌节内的细丝调节单位（RU）引发的，然后允许肌球蛋白从相对的粗丝跨桥结合肌动蛋白并产生力。细丝之间的重叠量决定了有多少潜在的交叉桥能够结合，从而决定了肌节如何产生力。肌病和萎缩可通过限制细丝之间的跨桥相互作用来损害肌肉功能，这可在细丝的长度减少或RU功能被破坏时发生。为了研究细丝长度和RU密度的变化如何影响整体跨桥行为和力的产生，我们使用半肌节的空间显式计算模型模拟肌肉收缩。细丝罗斯从细丝的尖端均匀地禁用（以模拟较短的细丝长度）或在半肌节的整个长度上随机禁用。均匀和随机RU？帅呆了在最大和次最大激活期间，方案降低了整体力产生。随机敲除方案还导致力-pCa关系的钙敏感性和协同性降低。我们还发现，与均匀RU敲除或正常RU激活的条件相比，随机RU敲除的力发展速率减慢。这些研究结果意味着，RU密度和力的生产肌节内的关系涉及更复杂的协调比简单的原始数量的罗斯可用于肌球蛋白跨桥绑定，并在其中可激活的RU分布在整个肌节的空间格局影响力的生产动态。
Striated muscle contraction is initiated by Ca2+ binding to, and activating, thin filament regulatory units (RU) within the sarcomere, which then allows myosin cross-bridges from the opposing thick filament to bind actin and generate force. The amount of overlap between the filaments dictates how many potential cross-bridges are capable of binding, and thus how force is generated by the sarcomere. Myopathies and atrophy can impair muscle function by limiting cross-bridge interactions between the filaments, which can occur when the length of the thin filament is reduced or when RU function is disrupted. To investigate how variations in thin filament length and RU density affect ensemble cross-bridge behavior and force production, we simulated muscle contraction using a spatially explicit computational model of the half-sarcomere. Thin filament RUs were disabled either uniformly from the pointed end of the filament (to model shorter thin filament length) or randomly throughout the length of the half-sarcomere. Both uniform and random RU ?knockout? schemes decreased overall force generation during maximal and submaximal activation. The random knockout scheme also led to decreased calcium sensitivity and cooperativity of the force-pCa relationship. We also found that the rate of force development slowed with the random RU knockout, compared to the uniform RU knockout or conditions of normal RU activation. These findings imply that the relationship between RU density and force production within the sarcomere involves more complex coordination than simply the raw number of RUs available for myosin cross-bridge binding, and that the spatial pattern in which activatable RU are distributed throughout the sarcomere influences the dynamics of force production.