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

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.