Validation of recent theories of skeletal muscle contraction: experiments and modelling

骨骼肌收缩最新理论的验证：实验和建模

• 批准号: 405834662
• 负责人: Professor Dr. Christian Rode
• 金额: --
• 依托单位: Institut für Sportwissenschaft
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/405834662?language=en
• 关键词: Validation; recent; theories; skeletal; muscle

Muscle models are commonly used in the life sciences to actuate multi-body systems, and e.g. to better understand mechanical or metabolic principles of locomotion. Most of the muscle models used are based exclusively on both the classical sliding filament- and the crossbridge theory of muscle contraction. These models ignore the dependence of muscle force on the history of contraction (over- or underestimation of forces during and after active muscle shortening or lengthening, respectively). As a result, their force predictions deviate by up to 100% compared to experiments. Consequently, there is substantial uncertainty about the validity of statements derived with classical muscle models. In addition, kinetic and microstructural findings at short sarcomere lengths contradict the classical theories of muscle contraction. Both lead to a confusion regarding the relationship between structure and function of the muscle.The main goal of the project is the development of a structurally motivated muscle fibre model, which allows a quantitative understanding of the mechanisms involved in force development. This goal is realized by a close intertwining of experiments on isolated muscle fibres and modelling. By fibre experiments, effects of muscle architecture can be excluded (e.g., fibre angle change during contraction) and sarcomere lengths of serially ordered sarcomeres necessary for modelling can be measured. In a first step, the dependence of muscle strength on the contraction history is modelled considering different mechanisms. The contribution of an activation-dependent titin spring (that connects the myosin filament with the Z-disc), variable crossbridge forces, and sarcomere length inhomogeneities are examined. In a second step, a structurally consistent half-sarcomere model that describes the contraction behaviour of the fibre at short sarcomere lengths is further developed and parameterized. Innovative experiments (such as removal of tropomyosin and direct ATP activation to elucidate possible binding of titin-actin, fluorescence microscopy of myosin tips at short sarcomere lengths) allow a validation of the proposed mechanisms. The combination of the models developed in the first two steps in a comprehensive muscle fibre model allows the consistent prediction of muscle forces throughout the entire muscle fibre working range. This is the crucial step on the way to reliable, realistic muscle models and thus also to increased predictive quality of muscle-driven multi-body models.

肌肉模型通常在生命科学中用于驱动多体系统，例如更好地理解运动的机械或代谢原理。大多数使用的肌肉模型完全基于肌肉收缩的经典滑动丝理论和横桥理论。这些模型忽略了肌肉力量对收缩历史的依赖性（分别在主动肌肉缩短或延长期间和之后过度估计或低估了力量）。因此，与实验相比，他们的力预测偏差高达 100%。因此，经典肌肉模型得出的陈述的有效性存在很大的不确定性。此外，短肌节长度的动力学和微观结构发现与肌肉收缩的经典理论相矛盾。两者都会导致对肌肉结构和功能之间关系的混淆。该项目的主要目标是开发结构驱动的肌肉纤维模型，该模型可以定量理解力发展所涉及的机制。这一目标是通过对孤立的肌肉纤维和建模的紧密结合的实验来实现的。通过纤维实验，可以排除肌肉结构的影响（例如，收缩期间的纤维角度变化），并且可以测量建模所需的连续有序肌节的肌节长度。第一步，考虑不同的机制，对肌肉力量对收缩历史的依赖性进行建模。研究了激活依赖性肌动蛋白弹簧（将肌球蛋白丝与 Z 盘连接）、可变的横桥力和肌节长度不均匀性的贡献。第二步，进一步开发和参数化结构一致的半肌节模型，该模型描述短肌节长度下纤维的收缩行为。创新实验（例如去除原肌球蛋白和直接 ATP 激活以阐明肌动蛋白-肌动蛋白可能的结合，短肌节长度的肌球蛋白尖端的荧光显微镜）可以验证所提出的机制。将前两步开发的模型组合到综合肌纤维模型中，可以对整个肌纤维工作范围内的肌肉力量进行一致的预测。这是建立可靠、真实的肌肉模型以及提高肌肉驱动的多体模型的预测质量的关键一步。