Biophysical Society Thematic Meeting | Canterbury 2023

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

Monday Speaker Abstracts

INTEGRATION OF MULTIPLE EXPERIMENTS BY MULTISCALE COMPUTATIONAL MODELING Srboljub M Mijailovich 1 ; Momcilo Prodanovic 1,2,3 ; Michael Regnier 4 ; Corrado Poggesi 5 ; Thomas C Irving 6 ; Michael A Geeves 7 ; 1 FilamenTech, Inc, Newton, MA, USA 2 University of Kragujevac, Faculty of Engineering, Kragujevac, Serbia 3 Institute for Information Technologies. University of Kragujevac, Technical and Technological Sciences, Kragujevac, Serbia 4 University of Washington, Bioengineering, Seattle , WA, USA 5 University of Florence, Experimental & Clinical Medicine, Florence, Italy ten orders of magnitude. A major difficulty, however, is relating these valuable bits of information from different experimental setups to relevant in vivo observations for assessing disease progression or the effectiveness of appropriate drugs and treatments. Recent multiscale computational modeling approaches that integrate information from a wide range of experiments can provide a deeper understanding of muscle functionality and its impact on human health. Spatially explicit stochastic models such as MUSICO platform enable translation of data from sub-molecular structural and biochemical information to muscle fiber dynamic functional behavior. The platform provides a powerful tool for quantitatively assessing the consequences of mutations in sarcomeric proteins, and the effects of Ca 2+ and small molecule therapeutics by incorporating detailed 3D structural information, crossbridge cycling kinetics, thin and thick filament regulation, and effect of accessory proteins including titin, nebulin and MyBP-C. This modeling approach successfully quantified the effects of (1) mutations in regulatory protein troponin-C and myosin; (2) differences in myosin isoforms across species, including humans; (3) transitions to and from an inactive myosin “parked state” governed by [Ca 2+ ] and thick filament sensitivity to force; role of (4) nebulin in nemaline myopathy; (5) roles of titin and interfilament spacing in length dependent activation; (6) interactions of MyBP-C with actin filaments and myosin in hypertrophic cardiomyopathy; and (7) the effects of drugs including mavacamten, 2 deoxyATP, disopyramide and digoxin. The mechanisms of these molecular modulations when translated to muscle fibers can be used for simulations of whole organ function using Finite Element solvers where instantaneous muscle material characteristics are assessed via computationally effective surrogate models. 6 Illinois Institute of Technology, Biology, Chicago, IL, USA 7 University of Kent, Biosciences, Canterbury, United Kingdom Research on the structure and function of muscle and how this relates to muscle disease has generated a vast quantity of data spanning multiple spatial and temporal scales differing by up to

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