Computational Tool to Study Perturbations In Muscle Regulation and Its Application To Heart Disease

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2019 May 26

PMID 31126584

Citations 12

Authors

Samantha K Barrick

Sarah R Clippinger

Lina Greenberg

Michael J Greenberg

Affiliations

Soon will be listed here.

Abstract

Striated muscle contraction occurs when myosin thick filaments bind to thin filaments in the sarcomere and generate pulling forces. This process is regulated by calcium, and it can be perturbed by pathological conditions (e.g., myopathies), physiological adaptations (e.g., β-adrenergic stimulation), and pharmacological interventions. Therefore, it is important to have a methodology to robustly determine the impact of these perturbations and statistically evaluate their effects. Here, we present an approach to measure the equilibrium constants that govern muscle activation, estimate uncertainty in these parameters, and statistically test the effects of perturbations. We provide a MATLAB-based computational tool for these analyses, along with easy-to-follow tutorials that make this approach accessible. The hypothesis testing and error estimation approaches described here are broadly applicable, and the provided tools work with other types of data, including cellular measurements. To demonstrate the utility of the approach, we apply it to elucidate the biophysical mechanism of a mutation that causes familial hypertrophic cardiomyopathy. This approach is generally useful for studying muscle diseases and therapeutic interventions that target muscle contraction.

Citing Articles

Structural dynamics of the intrinsically disordered linker region of cardiac troponin T.

Cubuk J, Greenberg L, Greenberg A, Emenecker R, Stuchell-Brereton M, Holehouse A bioRxiv. 2024; .

PMID: 38853835 PMC: 11160775. DOI: 10.1101/2024.05.30.596451.

Harnessing molecular mechanism for precision medicine in dilated cardiomyopathy caused by a mutation in troponin T.

Greenberg L, Stump W, Lin Z, Bredemeyer A, Blackwell T, Han X bioRxiv. 2024; .

PMID: 38645235 PMC: 11030379. DOI: 10.1101/2024.04.05.588306.

Single-molecule mechanics and kinetics of cardiac myosin interacting with regulated thin filaments.

Clippinger Schulte S, Scott B, Barrick S, Stump W, Blackwell T, Greenberg M Biophys J. 2023; 122(12):2544-2555.

PMID: 37165621 PMC: 10323011. DOI: 10.1016/j.bpj.2023.05.008.

Functional assays reveal the pathogenic mechanism of a de novo tropomyosin variant identified in patient with dilated cardiomyopathy.

Barrick S, Garg A, Greenberg L, Zhang S, Lin C, Stitziel N J Mol Cell Cardiol. 2023; 176:58-67.

PMID: 36739943 PMC: 11285302. DOI: 10.1016/j.yjmcc.2023.01.014.

Myofilament glycation in diabetes reduces contractility by inhibiting tropomyosin movement, is rescued by cMyBPC domains.

Papadaki M, Kampaengsri T, Barrick S, Campbell S, von Lewinski D, Rainer P J Mol Cell Cardiol. 2021; 162:1-9.

PMID: 34487755 PMC: 8766917. DOI: 10.1016/j.yjmcc.2021.08.012.

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