Abstract
Point mutations to the human gene TPM1 have been implicated in the development of both hypertrophic and dilated cardiomyopathies. Such observations have led to studies investigating the link between single residue changes and the biophysical behavior of the tropomyosin molecule. However, the degree to which these molecular perturbations explain the performance of intact sarcomeres containing mutant tropomyosin remains uncertain. Here, we present a modeling approach that integrates various aspects of tropomyosin's molecular properties into a cohesive paradigm representing their impact on muscle function. In particular, we considered the effects of tropomyosin mutations on (1) persistence length, (2) equilibrium between thin filament blocked and closed regulatory states, and (3) the crossbridge duty cycle. After demonstrating the ability of the new model to capture Ca-dependent myofilament responses during both dynamic and steady-state activation, we used it to capture the effects of hypertrophic cardiomyopathy (HCM) related E180G and D175N mutations on skinned myofiber mechanics. Our analysis indicates that the fiber-level effects of the two mutations can be accurately described by a combination of changes to the three tropomyosin properties represented in the model. Subsequently, we used the model to predict mutation effects on muscle twitch. Both mutations led to increased twitch contractility as a consequence of diminished cooperative inhibition between thin filament regulatory units. Overall, simulations suggest that a common twitch phenotype for HCM-linked tropomyosin mutations includes both increased contractility and elevated diastolic tension.
Highlights
Point mutations in alpha tropomyosin (TPM1) are associated with inherited cardiomyopathies, most notably hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (Redwood and Robinson, 2013)
Making use of published data, we found that the model was capable of capturing steady-state behavior of cardiac muscle preparations containing wild-type and mutant tropomyosins
To determine whether the model could still lead to behavior consistent with realistic calcium activation of muscle, we used constrained particle swarm optimization to find a set of parameters (Table 1, Set 1) that accurately matched calcium-dependent steady-state force production reported in skinned rat trabeculae (Figure 2; Dobesh et al, 2002)
Summary
Point mutations in alpha tropomyosin (TPM1) are associated with inherited cardiomyopathies, most notably hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (Redwood and Robinson, 2013). Studies on the classic HCM-related tropomyosin mutants E180G and D175N (Thierfelder et al, 1994) using electron microscopy, atomic force microscopy, and molecular dynamics on isolated tropomyosin have shown increased local and global flexibility (Li et al, 2010, 2012; Loong et al, 2012b). The surface interactions of tropomyosin and actin may affect myosin crossbridge formation, as suggested by length perturbation analysis studies (Bai et al, 2011). Based on these observations, we posit that emergent physiological effects of tropomyosin mutations can be described by considering the effects of residue changes on both the chain-like properties of the tropomyosin molecule and interaction of tropomyosin with the actin surface as it fluctuates between regulatory states. The simulations suggest that HCM-related tropomyosin mutations produce hypercontractile twitch phenotypes with diastolic dysfunction
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
