Mutation-Specific Cardiac Modeling

From sarcomere mutations to whole-heart functional prediction

From genetics to cardiac contraction

Inherited cardiomyopathies can arise from small changes in sarcomeric proteins. Using the MUSICO platform, we simulated how troponin C mutations associated with hypertrophic (HCM) and dilated (DCM) cardiomyopathies alter contraction, relaxation, and twitch behavior in cardiac muscle.

Key findings:

1
Troponin C mutations: L48Q associated with HCM and I61Q associated with DCM were modeled through the MUSICO workflow.
2
Muscle-level prediction: mutation-specific changes in twitch tension and relaxation behavior were predicted.
3
Thin-filament incorporation: varying levels of mutant incorporation changed the simulated contractile response.
4
Mechanistic translation: the workflow links genotype-level changes to functional cardiac consequences.
5
Research implication: enables mutation-specific disease interpretation and therapeutic hypothesis generation.

This case study shows how MUSICO connects genetic variation to predicted contractile behavior in cardiac muscle.

Reference:
Mijailovich et al., Journal of Molecular and Cellular Cardiology 155 (2021) 112–124

MUSICO-simulated twitch tension transients (dashed) compared to experimental data (solid) for wildtype and two cTnC mutations in transgenic mouse cardiac trabeculae. L48Q (HCM-related) increases peak tension and slows relaxation; I61Q (DCM-related) markedly reduces peak tension, both reproduced by adjusting only the Ca²⁺ dissociation rate and cTnC–cTnI affinity.
(Top) Cardiac troponin C (cTnC) ribbon structure showing the locations of the L48Q (green, HCM) and I61Q (blue, DCM) mutation sites within the calcium-binding domain. (Bottom) Schematic representation of thin filament mutation incorporation: wildtype (all red), 30% L48Q (mixed), and 50% I61Q (mixed). MUSICO explicitly models each protein position along the filament, enabling simulation of any incorporation level and spatial distribution.
MUSICO-predicted twitch tension transients (top) and key contractile parameters, time to peak tension (TTP), time to 50% and 90% relaxation (RT50, RT90), as a function of increasing mutation incorporation from 0% to 100% for cTnCI61Q (left) and cTnCL48Q (right). The simulations show that even low incorporation levels of I61Q produce significant functional changes, while L48Q effects scale more gradually, a distinction currently impossible to assess experimentally.
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