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In Vitro Assessment of Cardiac Function Using Skinned Cardiomyocytes
Published on: June 22, 2020
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Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its
Petr G Vikhorev1, Natalia N Vikhoreva2, WaiChun Yeung1
1National Heart and Lung Institute, Imperial College London, Du Cane Road, London W12 0NN, UK.
Cardiovascular Research
|November 2, 2020
Summary
Titin gene mutations in dilated cardiomyopathy reduce myofibril length-dependent activation and increase elasticity. Altered protein phosphorylation and Z-disk protein expression contribute to these changes in heart muscle function.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetics of Heart Disease
Background:
- Dilated cardiomyopathy (DCM) is frequently linked to mutations in sarcomere protein genes, with truncating mutations in the titin gene (TTN) being the most common.
- Understanding the functional consequences of TTN-truncating variants is crucial for elucidating DCM pathogenesis.
Purpose of the Study:
- To investigate the functional impact of TTN-truncating mutations on myofibril mechanics and cellular signaling in DCM.
- To characterize alterations in Ca2+ sensitivity, length-dependent activation, and protein expression profiles associated with TTN mutations.
Main Methods:
- Isolation and functional assessment of myofibrils from DCM hearts with TTN mutations and donor controls.
- Measurement of force, adenosine triphosphate (ATP) consumption, and Ca2+ sensitivity in skinned cardiomyocytes.
- Manipulation of protein phosphorylation and mRNA sequencing for gene expression analysis.
Main Results:
- DCM myofibrils with TTN mutations exhibited significantly higher Ca2+ sensitivity and absent length-dependent activation compared to controls.
- Phosphorylation levels of troponin I (TnI) and myosin binding protein-C (MyBP-C) were reduced in DCM ventricles.
- Down-regulation of Z-disk protein genes and up-regulation of MYL7 were observed in DCM patients with TTN variants.
Conclusions:
- TTN-truncating mutations alter myofibril mechanics, leading to decreased length-dependent activation and increased elasticity.
- Reduced phosphorylation of key regulatory proteins and altered Z-disk protein expression contribute to DCM pathophysiology.
- These findings highlight the complex interplay of genetic mutations and cellular changes in the development of dilated cardiomyopathy.
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