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

尽管取得了巨大的成功，但肌肉收缩的滑动细丝理论已被证明不足以解释肌肉功能的几个众所周知的重要方面，包括：1)通过拉伸增强力，2)通过缩短降低力，3)主动拉伸时产生力的低成本，以及4)主动缩短肌肉的高热力学效率。解释这些特性的努力产生了许多可供选择的假设。最近的研究表明，巨蛋白titin可能在活跃的横纹肌中起着弹簧的作用。仍然存在的重要问题是，titin弹簧是否可能在钙激活肌肉的收缩中起直接作用，如果是，是如何起作用的？“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，titin有助于肌肉收缩。它假定titin与钙活化肌节中的细丝结合。钙离子依赖的结合，以细丝阻止低力拉直的titin，通常发生在被动拉伸骨骼肌原纤维松弛长度，并解释心脏和骨骼肌之间的差异，在长度依赖的主动力。由于titin同时与粗丝和细丝结合，通过交叉桥旋转细丝会将titin缠绕在细丝上。在等距力发展过程中，将钛锡缠绕在细丝上，增加钛锡的应变和刚度，从而将弹性势能储存在未结合的钛锡中。细丝旋转引起的titin的应变和刚度变化的大小取决于titin的缠绕角度。在等距力展开过程中储存在titin中的弹性能量在主动缩短过程中得到恢复，从而提高缩短速度和功率输出。缠绕纤维模型有可能彻底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，甚至可能是人工心脏。拟议研究的目标是发展和测试的假设，即在细丝上缠绕的titin有助于肌肉力量的发展和主动缩短。这一目标将通过三个目标来实现。(1)继续开展实验工作，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丝模型的自稳定致动器。(3)开展新的合作，利用纳米技术测试缠绕丝模型，建立基于缠绕丝概念的数学和物理模型，并与工业界合作开发和制造用于机器人和假肢的自稳定致动器。这一提议的广泛影响包括生物学家、数学家、机械工程师和工业界之间跨学科合作的发展。提出的研究有可能通过促进轻量级致动器的发展而造福社会，这些致动器具有与活动肌肉非常相似的特性，包括在负载扰动期间的自稳定。代表性不足的学生，特别是西班牙裔和美洲原住民学生，将作为智力伙伴参与拟议的研究。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、工程和数学领域的跨学科会议来传播给广泛的受众。

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.