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，但已被证明不足以解释肌肉功能的几个长期已知和重要的方面，包括：1）拉伸力的增强，2）缩短力的抑制，3）主动拉伸期间力产生的低成本，以及4）主动缩短肌肉的高热力学效率。为了解释这些特性，人们提出了许多不同的假设。最近的研究表明，巨大的蛋白质肌联蛋白可能作为一个弹簧在活跃的横纹肌。剩下的重要问题是，肌联蛋白弹簧是否可能在钙激活肌肉的收缩中发挥直接作用，如果是这样，又是如何发挥作用的？“缠绕细丝”模型提供了肌联蛋白促进肌肉收缩的简单而全面的机制。它假定肌联蛋白与钙激活的肌节中的细丝结合。钙依赖性结合肌联蛋白的细丝，防止低力拉直肌联蛋白，通常发生在被动拉伸骨骼肌原纤维在松弛长度，并解释了心肌和骨骼肌之间的差异，在长度依赖性的主动力。因为肌联蛋白与粗丝和细丝都结合，所以细丝通过横桥的旋转将肌联蛋白缠绕在细丝上。肌联蛋白在细丝上的缠绕将通过在等长力发展期间增加其应变和刚度来在未结合的肌联蛋白中存储弹性势能。由于细丝旋转而引起的肌联蛋白的应变和刚度的变化幅度将取决于肌联蛋白的缠绕角度。在等长收缩力发展过程中储存在肌联蛋白中的弹性能在主动缩短过程中恢复，增加缩短速度和功率输出。缠绕细丝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hearts.The拟议研究的目标是开发和测试的假设，肌联蛋白上的细丝缠绕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)继续实验工作，以发展，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细丝模型的自稳定执行器。(3)发展新的合作，使用纳米技术测试缠绕细丝模型，创建基于缠绕细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执行器。该提案的更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。拟议的研究有可能通过促进具有与活动肌肉非常相似的特性的轻质致动器的开发来造福社会，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，将作为智力合作伙伴参加拟议的研究。这项研究的结果将通过在各种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大受众。

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.