Title: Cardiac troponin T N-domain variant destabilizes the actin interface resulting in disturbed myofilament function

Abstract

Missense variant Ile79Asn in human cardiac troponin T (cTnT-I79N) has been associated with hypertrophic cardiomyopathy and sudden cardiac arrest in juveniles. cTnT-I79N is located in the cTnT N-terminal (TnT1) loop region and is known for its pathological and prognostic relevance. A recent structural study revealed that I79 is part of a hydrophobic interface between the TnT1 loop and actin, which stabilizes the relaxed (OFF) state of the cardiac thin filament. Given the importance of understanding the role of TnT1 loop region in Ca ²⁺ regulation of the cardiac thin filament along with the underlying mechanisms of cTnT-I79N-linked pathogenesis, we investigated the effects of cTnT-I79N on cardiac myofilament function. Transgenic I79N (Tg-I79N) muscle bundles displayed increased myofilament Ca ²⁺ sensitivity, smaller myofilament lattice spacing, and slower crossbridge kinetics. These findings can be attributed to destabilization of the cardiac thin filament’s relaxed state resulting in an increased number of crossbridges during Ca ²⁺ activation. Additionally, in the low Ca ²⁺ -relaxed state (pCa8), we showed that more myosin heads are in the disordered-relaxed state (DRX) that are more likely to interact with actin in cTnT-I79N muscle bundles. Dysregulation of the myosin super-relaxed state (SRX) and the SRX/DRX equilibrium in cTnT-I79N muscle bundlesmore » likely result in increased mobility of myosin heads at pCa8, enhanced actomyosin interactions as evidenced by increased active force at low Ca ²⁺ , and increased sinusoidal stiffness. These findings point to a mechanism whereby cTnT-I79N weakens the interaction of the TnT1 loop with the actin filament, which in turn destabilizes the relaxed state of the cardiac thin filament.« less

Authors:

Landim-Vieira, Maicon  ^[1];

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Ma, Weikang  ^[2];

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Song, Taejeong  ^[3];

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Rastegarpouyani, Hosna  ^[4];

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Gong, Henry ^[2]; Coscarella, Isabella Leite ^[1]; Bogaards, Sylvia J. P.  ^[5];

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• Search DOE PAGES for ORCID "0000-0002-7127-3458"

Conijn, Stefan P. ^[5]; Ottenheijm, Coen A. C.  ^[5];

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Hwang, Hyun S.  ^[6];

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Papadaki, Maria ^[7]; Knollmann, Bjorn C.  ^[8];

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Sadayappan, Sakthivel  ^[3];

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Irving, Thomas C.  ^[2];

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Galkin, Vitold E.  ^[9];

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Chase, P. Bryant  ^[10];

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Pinto, Jose Renato ^[1]

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+ Show Author Affiliations

1. Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306
2. Department of Biology, Illinois Institute of Technology, Chicago, IL 60616
3. Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267
4. Department of Biological Science, Florida State University, Tallahassee, FL 32306, Institude of Molecular Biophysics, Florida State University, Tallahassee, FL 32306
5. Department of Physiology, Amsterdam University Medical Center, Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
6. Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL 32306
7. Department of Cell and Molecular Physiology, Loyola University Chicago Stritch School of Medicine, Chicago, IL 60153
8. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
9. Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23507
10. Department of Biological Science, Florida State University, Tallahassee, FL 32306

Publication Date:

Tue May 30 00:00:00 EDT 2023

Sponsoring Org.:

USDOE

OSTI Identifier:

2001355

Grant/Contract Number:  

AC02-06CH11357

Resource Type:

Published Article

Journal Name:

Proceedings of the National Academy of Sciences of the United States of America

Additional Journal Information:

Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 120 Journal Issue: 23; Journal ID: ISSN 0027-8424

Publisher:

Proceedings of the National Academy of Sciences

Country of Publication:

United States

Language:

English