Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Poster Abstracts

16-POS Board 16 A MATHEMATICAL MODEL OF THE DUAL-FILAMENT REGULATION FEEDBACK SYSTEM IN SKELETAL MUSCLE Lorenzo Marcucci 1,2 ; Luca Fusi 3,4 ; 1 University of Padova, 1Department of Biomedical Sciences, Padova, Italy 2 RIKEN, Center for Biosystems Dynamics Research, Suita, Japan 3 King’s College London, Randall Centre for Cell and Molecular Biophysics, London, United Kingdom 4 King’s College London, Centre for Human and Applied Physiology, London, United Kingdom Beside the classic calcium-mediated regulation of muscle contraction, driven by structural changes in the thin filaments regulatory proteins, a second pathway is emerging, based on the activation of the thick filaments, whose myosin motors in the relaxed state are in an auto inhibited configuration, lying along its surface. The proposed mechanosening mechanism postulates that the level of activation of the thick filament is regulated by the level of tension which it sustains. Therefore, few constitutively active motors can sense the activation of the thin filaments and generate force through the actomyosin cyclical interaction, which in turns activates the remaining motors in a cooperative way. Moreover, attached myosin motors can further stabilize the active conformation of the thin filament regulatory proteins, forming a two-way feedback system. This two-way feedback system increases the complexity of the fine regulation of muscle contraction, making it adaptable to a variety of tasks, but also obscuring its role in the physiological contraction. In this respect, mathematical modeling is useful to dissect the role of the different components of the muscle regulation. Here, we combine mechanical and structural data during activation in near-physiological conditions, using calcium jumps produced by photolysis of caged calcium and probes on myosin in the thick filaments to monitor its activation states, with a mathematical model which includes the mechanosening mechanism tightly constrained on the activation rates previously observed under passive forces on the same muscle and conditions. Quantitative simulations suggest that the initial phases of contraction are driven by about a 35% of constitutively active motors, a value coherent with previous estimations. However, at filament stresses higher than 0.5 T0, the model without a myosin-induced activation of the thin filament predicts a slower activation of the thick filament with a reduced fitting of the rate of force development. A discrepancy can also be seen in the experimental data comparing the rate of force development and re-development after a fast, small, imposed shortening at T0. We show that including the two-way feedback is necessary to properly describe muscle force generation during a tetanic contraction.

72