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

肌肉模型通常用于生命科学中，以驱动多体系统，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经典的滑动细丝和肌肉收缩的交叉桥理论。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或低估力量）。因此，他们的力预测与实验相比偏差高达100%。因此，用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，在短肌节长度的动力学和微观结构的研究结果相矛盾的肌肉收缩的经典理论。这两种方法都导致了肌肉结构和功能之间关系的混乱。该项目的主要目标是开发一种结构驱动的肌肉纤维模型，从而可以定量地了解力量发展所涉及的机制。这一目标是通过对分离的肌肉纤维和建模的实验的紧密交织来实现的。通过纤维实验，可以排除肌肉结构的影响（例如，收缩期间的纤维角变化）和建模所需的连续排列的肌节的肌节长度。在第一步中，肌肉力量对收缩历史的依赖性被建模，考虑不同的机制。激活依赖肌联蛋白弹簧（连接肌球蛋白丝与Z-盘），可变的crossbridge力，和肌节长度不均匀性的贡献进行了检查。在第二步中，进一步开发和参数化结构一致的半肌节模型，该模型描述了短肌节长度下纤维的收缩行为。创新的实验（如去除原肌球蛋白和直接ATP激活，以阐明可能的结合肌联蛋白-肌动蛋白，荧光显微镜的肌球蛋白提示在短肌节长度）允许验证所提出的机制。在前两步中开发的模型组合在一个全面的肌纤维模型中，可以在整个肌纤维工作范围内一致地预测肌肉力量。这是通往可靠、逼真的肌肉模型的关键一步，也是提高肌肉驱动的多体模型预测质量的关键一步。

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.