Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility

Jenni Laitila; Christopher T.A. Lewis; Anthony L. Hessel; Guido Primiano; Aurelio Hernandez-Lain; Chiara Fiorillo; Michael W. Lawlor; Coen A.C. Ottenheijm; Heinz Jungbluth; Ka Fu Man; Arianna Fornili; Julien Ochala

doi:10.1113/JP288109

Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility

Jenni Laitila, Christopher T.A. Lewis, Anthony L. Hessel, Guido Primiano, Aurelio Hernandez-Lain, Chiara Fiorillo, Michael W. Lawlor, Coen A.C. Ottenheijm, Heinz Jungbluth, Ka Fu Man, Arianna Fornili, Julien Ochala^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Abstract: In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the TNNT1 and TNNT3 genes, respectively. Nonsense or missense TNNT1 variants have been associated with skeletal muscle weakness and contractures and a histopathological appearance of nemaline myopathy (NM) on muscle biopsy. Little is known about how TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of targeted therapeutic interventions. Here, we aimed to identify the underlying molecular biophysical mechanisms, by investigating isolated skeletal myofibres from patients with TNNT1-related NM as well as from controls through a combination of structural and functional assays. Our studies revealed variable and unusual ssTnT and fsTnT expression patterns and post-translational modifications. We also observed that, in the presence of TNNT1 variants, the thin filament was more compliant, and this was associated with a higher myofibre Ca²⁺ sensitivity. Altogether, our findings suggest TnT remodelling as the key mechanism ultimately leading to molecular and cellular hyper-contractility, and then inhibitors of altered contractility as potential therapeutic modalities for TNNT1-associated NM. (Figure presented.). Key points: No therapeutic treatment exists for patients with genetic TNNT1 mutations and skeletal muscle weakness/contractures. In these patients, expression and post-translational modifications of troponin T are severely disrupted. These are associated with changes in thin filament compliance where troponin T is located. All these induce muscle fibre hyper-contractility that can be reversed by mavacamten, a myosin ATPase inhibitor.

Original language	English
Pages (from-to)	3533-3550
Number of pages	18
Journal	Journal of Physiology
Volume	603
Issue number	12
Early online date	5 May 2025
DOIs	https://doi.org/10.1113/JP288109
Publication status	Published - 15 Jun 2025

Keywords

congenital myopathy
contracture
force
skeletal muscle
troponin

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Pathogenic TNNT1 variants_LAITILA_Publishedonline15April2025_GOLD VoR (CC-BY)Final published version, 3.32 MBLicence: CC BY

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Laitila, J., Lewis, C. T. A., Hessel, A. L., Primiano, G., Hernandez-Lain, A., Fiorillo, C., Lawlor, M. W., Ottenheijm, C. A. C., Jungbluth, H., Man, K. F., Fornili, A., & Ochala, J. (2025). Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility. Journal of Physiology, 603(12), 3533-3550. https://doi.org/10.1113/JP288109

@article{a2704bf3732645678aeb7b86906257c7,

title = "Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility",

abstract = "Abstract: In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the TNNT1 and TNNT3 genes, respectively. Nonsense or missense TNNT1 variants have been associated with skeletal muscle weakness and contractures and a histopathological appearance of nemaline myopathy (NM) on muscle biopsy. Little is known about how TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of targeted therapeutic interventions. Here, we aimed to identify the underlying molecular biophysical mechanisms, by investigating isolated skeletal myofibres from patients with TNNT1-related NM as well as from controls through a combination of structural and functional assays. Our studies revealed variable and unusual ssTnT and fsTnT expression patterns and post-translational modifications. We also observed that, in the presence of TNNT1 variants, the thin filament was more compliant, and this was associated with a higher myofibre Ca2+ sensitivity. Altogether, our findings suggest TnT remodelling as the key mechanism ultimately leading to molecular and cellular hyper-contractility, and then inhibitors of altered contractility as potential therapeutic modalities for TNNT1-associated NM. (Figure presented.). Key points: No therapeutic treatment exists for patients with genetic TNNT1 mutations and skeletal muscle weakness/contractures. In these patients, expression and post-translational modifications of troponin T are severely disrupted. These are associated with changes in thin filament compliance where troponin T is located. All these induce muscle fibre hyper-contractility that can be reversed by mavacamten, a myosin ATPase inhibitor.",

keywords = "congenital myopathy, contracture, force, skeletal muscle, troponin",

author = "Jenni Laitila and Lewis, {Christopher T.A.} and Hessel, {Anthony L.} and Guido Primiano and Aurelio Hernandez-Lain and Chiara Fiorillo and Lawlor, {Michael W.} and Ottenheijm, {Coen A.C.} and Heinz Jungbluth and Man, {Ka Fu} and Arianna Fornili and Julien Ochala",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.",

year = "2025",

month = jun,

day = "15",

doi = "10.1113/JP288109",

language = "English",

volume = "603",

pages = "3533--3550",

journal = "Journal of Physiology",

issn = "0022-3751",

publisher = "Wiley",

number = "12",

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TY - JOUR

T1 - Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility

AU - Laitila, Jenni

AU - Lewis, Christopher T.A.

AU - Hessel, Anthony L.

AU - Primiano, Guido

AU - Hernandez-Lain, Aurelio

AU - Fiorillo, Chiara

AU - Lawlor, Michael W.

AU - Ottenheijm, Coen A.C.

AU - Jungbluth, Heinz

AU - Man, Ka Fu

AU - Fornili, Arianna

AU - Ochala, Julien

PY - 2025/6/15

Y1 - 2025/6/15

N2 - Abstract: In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the TNNT1 and TNNT3 genes, respectively. Nonsense or missense TNNT1 variants have been associated with skeletal muscle weakness and contractures and a histopathological appearance of nemaline myopathy (NM) on muscle biopsy. Little is known about how TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of targeted therapeutic interventions. Here, we aimed to identify the underlying molecular biophysical mechanisms, by investigating isolated skeletal myofibres from patients with TNNT1-related NM as well as from controls through a combination of structural and functional assays. Our studies revealed variable and unusual ssTnT and fsTnT expression patterns and post-translational modifications. We also observed that, in the presence of TNNT1 variants, the thin filament was more compliant, and this was associated with a higher myofibre Ca2+ sensitivity. Altogether, our findings suggest TnT remodelling as the key mechanism ultimately leading to molecular and cellular hyper-contractility, and then inhibitors of altered contractility as potential therapeutic modalities for TNNT1-associated NM. (Figure presented.). Key points: No therapeutic treatment exists for patients with genetic TNNT1 mutations and skeletal muscle weakness/contractures. In these patients, expression and post-translational modifications of troponin T are severely disrupted. These are associated with changes in thin filament compliance where troponin T is located. All these induce muscle fibre hyper-contractility that can be reversed by mavacamten, a myosin ATPase inhibitor.

AB - Abstract: In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the TNNT1 and TNNT3 genes, respectively. Nonsense or missense TNNT1 variants have been associated with skeletal muscle weakness and contractures and a histopathological appearance of nemaline myopathy (NM) on muscle biopsy. Little is known about how TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of targeted therapeutic interventions. Here, we aimed to identify the underlying molecular biophysical mechanisms, by investigating isolated skeletal myofibres from patients with TNNT1-related NM as well as from controls through a combination of structural and functional assays. Our studies revealed variable and unusual ssTnT and fsTnT expression patterns and post-translational modifications. We also observed that, in the presence of TNNT1 variants, the thin filament was more compliant, and this was associated with a higher myofibre Ca2+ sensitivity. Altogether, our findings suggest TnT remodelling as the key mechanism ultimately leading to molecular and cellular hyper-contractility, and then inhibitors of altered contractility as potential therapeutic modalities for TNNT1-associated NM. (Figure presented.). Key points: No therapeutic treatment exists for patients with genetic TNNT1 mutations and skeletal muscle weakness/contractures. In these patients, expression and post-translational modifications of troponin T are severely disrupted. These are associated with changes in thin filament compliance where troponin T is located. All these induce muscle fibre hyper-contractility that can be reversed by mavacamten, a myosin ATPase inhibitor.

KW - congenital myopathy

KW - contracture

KW - force

KW - skeletal muscle

KW - troponin

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U2 - 10.1113/JP288109

DO - 10.1113/JP288109

M3 - Article

AN - SCOPUS:105004323909

SN - 0022-3751

VL - 603

SP - 3533

EP - 3550

JO - Journal of Physiology

JF - Journal of Physiology

IS - 12

ER -

Pathogenic TNNT1 variants are associated with aberrant thin filament compliance and myofibre hyper-contractility

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