SGER: Is titin a "winding filament"? A new twist on muscle contraction

尽管肌肉收缩的滑动细丝理论取得了巨大的成功，但事实证明，它不足以解释肌肉功能的几个早已为人所知的重要方面，包括：1)通过拉伸增强力量，2)通过缩短来抑制力量，3)在主动拉伸过程中产生低成本的力量，以及4)积极缩短肌肉的高热力学效率。解释这些性质的努力导致了许多不同的假设。最近的研究表明，巨大的蛋白质titin可能在活跃的横纹肌中起到弹簧的作用。仍然存在的重要问题是，Titin弹簧是否可能在钙激活的肌肉收缩中发挥直接作用，如果是的话，是如何发挥作用的？“缠绕细丝”模型提供了一种简单而全面的机制，通过这种机制，肌动蛋白有助于肌肉收缩。它假定Titin结合在钙激活的肌节中的细丝上。依赖于钙离子的Titin与细丝的结合阻止了通常发生在骨骼肌原纤维松弛长度的被动拉伸时的Titin的低力拉直，并解释了心肌和骨骼肌在主动力的长度依赖方面的差异。由于TiN既与粗丝捆绑，也与细丝捆绑在一起，所以跨桥旋转细丝会使TiN缠绕在细丝上。TiTiN缠绕在细丝上，通过在等长力发展过程中增加其应变和刚度，将弹性势能储存在未结合的TiTiN中。细丝旋转引起TiTiN的应变和硬度变化的幅度将取决于TiTiN的缠绕角度。在主动缩短过程中，在等长力发展过程中储存在Titin中的弹性能量被回收，从而提高了缩短速度和功率输出。缠绕细丝模型有可能改变肌肉生理学领域以及肌肉功能的数学和生物力学模型，影响执行器和假体的设计，甚至可能影响人工心脏的设计。本研究的目的是发展和验证这样一个假说，即在细丝上缠绕Titin有助于肌力的发展和主动缩短。这一目标将通过三个目标来实现。(1)继续进行实验工作，以开发、完善和测试模型的预测。(2)与机械工程师合作，开发基于缠绕纤维模型的自稳定执行器。(3)开展新的合作，利用纳米技术测试缠绕长丝模型，基于缠绕长丝概念创建数学和物理模型，并与行业合作开发和制造用于机器人和假肢应用的自稳定执行器。这项提议的更广泛的影响包括发展生物学家、数学家、机械工程师和工业之间的跨学科合作。拟议的研究有可能造福社会，因为它促进了轻量级执行器的开发，其特性与活动肌肉的特性非常相似，包括在负载扰动时的自我稳定。代表不足的学生，特别是西班牙裔和美国原住民学生，将作为智力合作伙伴参与拟议中的研究。这项研究的结果将通过在不同的媒体上发表和参加神经科学、工程学和数学领域的跨学科会议来向广大受众传播。

Despite its huge success, the sliding filament theory of muscle contraction has proven insufficient to explain several long-known and important aspects of muscle function, including: 1) enhancement of force with stretch, 2) depression of force with shortening, 3) the low cost of force production during active stretch, and 4) the high thermodynamic efficiency of actively shortening muscle. Efforts to explain these properties have led to numerous alternative hypotheses. Recent studies have suggested that the giant protein titin may function as a spring in active striated muscle. The important question that remains is whether a titin spring might play a direct role in contraction of calcium-activated muscle, and if so, how? The 'winding filament' model provides a simple and comprehensive mechanism by which titin contributes to muscle contraction. It postulates that titin binds to the thin filament in calcium-activated sarcomeres. Ca2+-dependent binding of titin to the thin filament prevents low-force straightening of titin that normally occurs upon passive stretch of skeletal myofibrils at slack length, and explains differences between cardiac and skeletal muscle in the length-dependence of active force. Because titin is bound to both the thick and thin filaments, rotation of the thin filament by the cross bridges will wind titin upon the thin filament. Winding of titin on the thin filament will store elastic potential energy in unbound titin by increasing its strain and stiffness during isometric force development. The magnitude of changes in strain and stiffness of titin due to thin filament rotation will depend on the winding angle of titin. The elastic energy stored in titin during isometric force development is recovered during active shortening, increasing shortening velocity and power output. The winding filament model has the potential to revolutionize the field of muscle physiology, as well as mathematical and biomechanical models of muscle function, influencing the design of actuators and prostheses, perhaps even artificial hearts.The goal of the proposed research is to develop and test the hypothesis that winding of titin upon the thin filament contributes to muscle force development and active shortening. That goal will be accomplished via three objectives. (1) Continue experimental work to develop, refine, and test predictions of the model. (2) Collaborate with mechanical engineers to develop self-stabilizing actuators based on the winding filament model. (3) Develop new collaborations to test the winding filament model using nanotechnology, to create mathematical and physical models based on the winding filament concept, and to collaborate with industry to develop and manufacture self-stabilizing actuators for applications in robotics and prosthetics. The broader impacts of this proposal include the development of interdisciplinary collaborations among biologists, mathematicians, mechanical engineers, and industry. The proposed studies have the potential to benefit society by facilitating the development of lightweight actuators with properties that closely resemble those of active muscle, including self-stabilization during perturbations in load. Underrepresented students, especially Hispanic and Native American students, will participate as intellectual partners in the proposed studies. The results of this research will be disseminated to a broad audience by publishing in diverse media and by participating in interdisciplinary conferences in the areas of neuroscience, engineering, and mathematics.