30P Nemaline myopathy-linked TNNT1 mutations are associated with aberrant thin filament extensibility and myofibre hyper-contractility

• Published in: Neuromuscular disorders : NMD Vol. 43; p. 104441
• Main Authors: Laitila, J., Lewis, C., Hessel, A., Primiano, G., Hernandez-Lain, A., Fiorillo, C., Lawlor, M., Ottenheijm, C., Ochala, J.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2024
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.237

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 mutations have been identified and associated with skeletal muscle weakness, fatigue and a condition named Nemaline Myopathy. Little is known about the underlying mechanisms by which these TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of appropriate therapeutic interventions. Here, we aimed to identify the molecular biochemical and biophysical mechanisms. For that, we isolated skeletal myofibres from Nemaline patients with known TNNT1 mutations as well as from age- and gender-matched controls. We then performed a combination of structural and functional assays. Besides the mutations, our studies revealed unusual ssTnT and fsTnT expressions and post-translational modifications (PTM). We also observed that, in the presence of TNNT1 mutations and aberrant PTMs, the relaxed thin filament was more compliant and extensible, mimicking the contraction state. This was accompanied by the production of higher forces at low calcium concentrations. Taken together, our findings highlight a potential TnT remodelling ultimately leading to molecular hyper-contractility. This then suggests the use of myosin/contractile inhibitors for the treatment of Nemaline Myopathy due to TNNT1 mutations.