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Myosin kinetics during shortening and lengthening in striated muscles

横纹肌缩短和延长过程中的肌球蛋白动力学

基本信息

批准号：
1656450
负责人：
Bertrand Tanner
金额：
$ 46.44万
依托单位：
Washington State University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1656450&HistoricalAwards=false
关键词：
Myosin kinetics during shortening lengthening

项目摘要

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.

日常活动，如走楼梯或携带一袋杂货，肌肉不断暴露于不同的负荷和激活水平，因为不同的肌肉缩短和延长。近世纪以来，研究表明，肌肉在缩短和延长过程中使用的能量不同。这项研究资金支持的研究将测试缩短和延长的整个肌肉特征如何与运动蛋白肌球蛋白分子活性的变化联系起来。从根本上说，肌球蛋白是分子马达，它将化学能转化为力量并缩短肌肉，从而为运动和血液流动提供动力。该提案的目标是测量、建模和预测收缩期间肌球蛋白活性如何随肌肉长度变化。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，并且对肌肉缩短和延长期间力产生和功率输出的分子现象的更好的机械理解将最终有助于确定从分子到组织和生物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的本科生和研究生的多元化。与美国原住民项目办公室和本科生研究办公室合作，推广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实现就业机会相结合的广泛潜力。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量产生。测量肌球蛋白率转换在完整的，电刺激骨骼肌和心肌将扩展到探针等长收缩，以及在延长和缩短的动态收缩。互补的皮肤纤维测量将能够测量肌纤维缩短和延长时的跨桥核苷酸处理速率。这些经验发现将与肌肉收缩的计算模型相结合，以更好地解释和预测肌球蛋白力产生和能量利用的影响，从分子到肌节，纤维和肌肉。这种原则性的定量方法将提供一个初步步骤，以确定横纹肌类型，肌球蛋白亚型和肌肉结构，最终影响横纹肌系统的功能多样性之间的相似性和差异。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiac myosin binding protein-C phosphorylation accelerates β-cardiac myosin detachment rate in mouse myocardium

心肌肌球蛋白结合蛋白-C 磷酸化加速小鼠心肌中β-心肌肌球蛋白脱离率

DOI：
10.1152/ajpheart.00673.2020
发表时间：
2021
期刊：
American Journal of Physiology-Heart and Circulatory Physiology
影响因子：
4.8
作者：
Tanner, Bertrand C.;Previs, Michael J.;Wang, Yuan;Robbins, Jeffrey;Palmer, Bradley M.
通讯作者：
Palmer, Bradley M.

Functional significance of C-terminal mobile domain of cardiac troponin I.