Myosin kinetics during shortening and lengthening in striated muscles

日常活动，如上楼或提一袋杂货，肌肉会不断地暴露在不同的负荷和激活水平下，因为不同的肌肉会变短或变长。近一个世纪以来，研究表明，肌肉在缩短和延长时使用的能量是不同的。这项研究基金支持的研究将测试整个肌肉的缩短和延长特征是如何与运动蛋白肌球蛋白分子活性的变化联系在一起的。从根本上说，肌凝蛋白是一种分子马达，它将化学能转化为肌肉的力量和收缩，从而为运动和血液流动提供动力。这一建议的目的是测量，建模，并预测肌凝蛋白活性如何随收缩期间肌肉长度的变化。横纹肌主要有三种类型：慢骨骼肌、快骨骼肌和心肌。这些肌肉类型具有明显不同的功能，对肌肉缩短和延长过程中力量产生和力量输出的分子现象的更好的机制理解将最终有助于确定从分子到组织和有机体水平的耦合的关键机制，从而实现运动。这些研究工作的一部分将继续培养生物物理和计算生物学研究方面的本科生和研究生。在与印第安人项目办公室和本科生研究办公室的合作下，外展和教育工作将告知当地学校和地区部落学院的学生，将他们的科学兴趣与令人满意的就业机会结合起来的广泛潜力。在拟议的研究中，生物物理系统分析将用于测量肌肉长度的动态变化如何影响肌球蛋白动力学和力的产生。在完整的、电刺激的骨骼肌和心肌中肌球蛋白速率转换的测量将扩展到探测等距收缩，以及在延长和缩短期间的动态收缩。互补皮纤维测量将使测量跨桥核苷酸处理速率的肌肉纤维缩短和延长。这些实证研究结果将与肌肉收缩的计算模型相结合，以更好地解释和预测肌凝蛋白力的产生和从分子到肌节、纤维和肌肉的能量利用的影响。这种原则性的定量方法将为确定横纹肌类型、肌球蛋白异构体和肌肉结构之间的异同提供初步的步骤，最终影响横纹肌系统的功能多样性。

Daily activities, such as walking up stairs or carrying a bag of groceries, muscles are constantly exposed to varying loads and levels of activation as different muscles shorten and lengthen. For nearly a century, studies have shown that muscles use energy differently during shortening versus lengthening. The studies supported by this research funding will test how whole-muscle characteristics of shortening and lengthening are linked to changes in the molecular activity of the motor protein, myosin. Fundamentally, myosin is the molecular motor that turn chemical energy into force and shortening in a muscle, thereby powering locomotion and blood flow. The goal of this proposal is to measure, model, and predict how myosin activity changes with muscle length during a contraction. There are three main types of striated muscle: slow skeletal muscle, fast skeletal muscle, and cardiac muscle. These muscle types have distinctly different functions, and a better mechanistic understanding of the molecular phenomena underlying force production and power output during muscle shortening and lengthening will ultimately help determine critical mechanisms of coupling from the molecule to the tissue and organism levels that enable movement. A portion of these research efforts will continue to train a diverse set of undergraduate and graduate students in biophysical and computational biology research. Outreach and educational efforts, in collaboration with the Native American Programs Office and Office of Undergraduate Research, will inform students at local schools and regional Tribal Colleges about the wide-ranging potential to integrate their scientific interests with fulfilling employment opportunities.In the proposed research, biophysical system analysis will be used to measure how dynamic changes in muscle length influence myosin kinetics and force generation. Measurements of myosin rate-transitions in intact, electrically stimulated skeletal and cardiac muscles will be extended to probe isometric contraction, as well as dynamic contractions during lengthening and shortening. Complementary skinned fiber measurements will enable measurements of cross-bridge nucleotide handling rates as muscle fibers shorten and lengthen. These empirical findings will be integrated with computational models of muscle contraction to better interpret and predict the impact of myosin force production and energy utilization from the molecule to the sarcomere, fiber, and muscle. This principled, quantitative approach will provide an initial step towards defining similarities and differences between striated muscle type, myosin isoform, and muscle structure that ultimately influence functional diversity of striated muscle systems.