Drug Effects on Human Cardiac Muscle Contraction and LV Function
How does a sarcomere-targeted drug change cardiac function at the whole-heart level? This case study demonstrates how MUSICO simulates the effects of mavacamten and disopyramide on human HCM cardiac muscle, translating molecular drug action into predicted left ventricular pressure-volume behavior. Starting from ATPase kinetics and fiber mechanics data, MUSICO reproduced experimental twitch tension and calcium transient data for both drugs, then passed sarcomere-level outputs to a finite element LV model. The results show distinct mechanisms: mavacamten acts through force reduction at the crossbridge level, while disopyramide works primarily through calcium transient modulation. Both drugs shift the LV pressure-volume loop toward more physiological function, directionally consistent with clinical hemodynamic data from HCM trials.
Cross-Species Cardiac Prediction
Animal models frequently fail to predict human cardiac drug response because myosin isoform composition differs fundamentally between species. This case study shows how MUSICO predicts cardiac twitch dynamics in mouse, rat, and human cardiac trabeculae using the same mechanistic parameter set, without refitting between species. The model accounts for the shift from predominantly fast alpha-myosin in rodents to predominantly slow beta-myosin in humans, the key molecular difference that conventional scaling approaches cannot capture. Predictions were validated against blinded experimental data at physiological temperature in all three species. This is the scientific standard for genuine forward prediction: parameters fitted once to rodent data, then used without adjustment to predict human cardiac behavior from animal model observations.
Mutation-Specific Cardiac Modeling
Genetic cardiomyopathies present a fundamental challenge: the same disease category contains patients with distinct molecular dysfunctions that respond differently to the same therapy. This case study shows how MUSICO models cardiac troponin C mutations L48Q (HCM-related) and I61Q (DCM-related) at the protein level, reproducing distinct contraction and relaxation phenotypes in transgenic mouse cardiac muscle by adjusting only calcium dissociation rate and troponin C-troponin I affinity. Beyond binary wildtype versus mutant comparisons, MUSICO simulates variable mutation incorporation levels along the thin filament, predicting how contractile function changes across the full range from 0% to 100% mutation expression. This capability enables patient-stratification hypotheses and compound screening decisions that experimental methods currently cannot support.
X-ray Diffraction Simulations
Synchrotron X-ray fiber diffraction is the most direct experimental window into myosin head states during muscle contraction and drug binding, but extracting quantitative mechanistic information from diffraction patterns has remained technically intractable. This case study introduces MUSICO-X, a computational module that predicts small-angle X-ray fiber diffraction patterns from MUSICO sarcomere simulations, enabling simultaneous validation of structural and functional predictions from the same experiment. Applied to contracted actin filaments, MUSICO-X reproduces meridional reflection patterns at 27.3, 13.6, and 9.1 angstrom using both all-atom and coarse-grained actin models. The approach allows quantification of local thin filament forces from diffraction data alone, a measurement inaccessible by any other experimental or analytical technique, directly relevant to structural validation of sarcomere-targeted drug mechanisms.
Skeletal Muscle Disease Modeling
Duchenne muscular dystrophy is caused by absence of dystrophin, the structural protein that transmits contractile forces between sarcomeres and the extracellular matrix. Without dystrophin, contraction-induced membrane damage accumulates with every muscle activation. This case study shows how MUSICO models the mechanical consequences of dystrophin deficiency in skeletal muscle, predicting shear strain distributions between fast and slow muscle fibers during loaded contraction in both normal and DMD conditions. Loss of dystrophin produces markedly elevated and heterogeneous shear strain at the fiber-matrix interface, directly consistent with the membrane damage hypothesis. Sarcomere-level tension predictions show directional consistency with multi-scale finite element results, validating the mechanistic framework across fiber types. The approach offers a computational entry point for evaluating dystrophin-restoration therapies before costly animal studies.
Airway Smooth Muscle and Lung Disease
Why does tidal breathing prevent dangerous airway narrowing in healthy lungs, but fail in asthma? The answer lies in the dynamics of myosin binding in airway smooth muscle, not in static force-length relationships. This case study presents computational modeling of airway smooth muscle mechanics using the Hai-Murphy latch regulatory scheme integrated with Huxley crossbridge dynamics, showing how oscillatory tidal stretches perturb myosin binding equilibrium and reduce active force in healthy airways. When smooth muscle mass increases through asthmatic remodeling, tidal stretch becomes insufficient to perturb myosin binding, stiffness rises through positive feedback, and the airway freezes in a latch state refractory to bronchodilation. These findings provide a mechanistic framework directly applicable to computational evaluation of bronchodilator therapies, smooth muscle mass reduction strategies, and COPD airway modeling.
New NIH grant awarded
FilamenTech is pleased to announce participation in a new NIH-funded scientific project: “Analysis Tools for Fiber Diffraction of Muscle” (R01GM144555), supported by the National Institute of General Medical Sciences of the National Institutes of Health. The project is led by Principal Investigator Prof. Thomas C. Irving from Illinois Institute of Technology and the BioCAT beamline at Argonne National Lab, with FilamenTech contributing computational simulation and data analysis capabilities. The collaboration connects MUSICO’s physics-based sarcomere modeling directly to synchrotron X-ray fiber diffraction experiments, enabling simultaneous structural and functional validation of muscle contraction mechanics. This NIH award supports the development of computational tools that extract quantitative mechanistic information from muscle diffraction data, including myosin head state populations directly relevant to the mechanism of action of sarcomere-targeted cardiac drugs.
Collaboration with IIT and NASA
FilamenTech has begun a scientific collaboration with Prof. Aleksandar G. Ostrogorsky from Illinois Institute of Technology on performing simulations and data analysis for the optimization of the DiGS (Diffraction in Gravity Studies) experiments conducted on Earth and aboard the International Space Station. The ISS provides a unique experimental environment for studying how sarcomere regulatory proteins change under altered gravitational loading — an accelerated model for muscle atrophy relevant to cardiomyopathy, skeletal muscle disease, and the mechanobiology of sarcomere dysfunction. FilamenTech’s MUSICO platform contributes computational interpretation of X-ray diffraction data from these microgravity experiments, connecting space-based structural observations to mechanistic predictions of muscle function under physiological and pathological conditions.
Successful completion of SilicoFCM EU project
FilamenTech co-founders Prof. Srboljub Mijailovich and Momčilo Prodanović, along with FilamenTech’s Scientific Advisory Board members, have successfully completed their participation in SilicoFCM, a four-year EU Horizon 2020 project focused on in silico trials for tracing the effects of sarcomeric protein mutations leading to familial cardiomyopathy (Grant No. 777204). The project established a multi-scale computational framework connecting sarcomere-level genetic mutations to whole-heart functional predictions, forming the scientific foundation for MUSICO’s current cardiac drug development applications. SilicoFCM validated the MUSICO platform across a range of HCM and DCM mutations, delivering peer-reviewed publications in Pharmaceutics, Biophysical Journal, and related journals. The successful completion of this Horizon 2020 program marks a major platform validation milestone and positions FilamenTech for the next phase of EU Horizon Europe engagement through the CHAINAM consortium proposal.
