KBTBD13 is an actin-binding protein that modulates muscle kinetics
Josine M. de Winter, … , Nicol C. Voermans, Coen A.C. Ottenheijm
Josine M. de Winter, … , Nicol C. Voermans, Coen A.C. Ottenheijm
Published October 31, 2019
Citation Information: J Clin Invest. 2020;130(2):754-767. https://doi.org/10.1172/JCI124000.
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Research Article Muscle biology

KBTBD13 is an actin-binding protein that modulates muscle kinetics

Abstract

The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation–induced muscle relaxation, muscle fiber– and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin — a major constituent of the thin filament — and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.

Authors

Josine M. de Winter, Joery P. Molenaar, Michaela Yuen, Robbert van der Pijl, Shengyi Shen, Stefan Conijn, Martijn van de Locht, Menne Willigenburg, Sylvia J.P. Bogaards, Esmee S.B. van Kleef, Saskia Lassche, Malin Persson, Dilson E. Rassier, Tamar E. Sztal, Avnika A. Ruparelia, Viola Oorschot, Georg Ramm, Thomas E. Hall, Zherui Xiong, Christopher N. Johnson, Frank Li, Balazs Kiss, Noelia Lozano-Vidal, Reinier A. Boon, Manuela Marabita, Leonardo Nogara, Bert Blaauw, Richard J. Rodenburg, Benno Küsters, Jonne Doorduin, Alan H. Beggs, Henk Granzier, Ken Campbell, Weikang Ma, Thomas Irving, Edoardo Malfatti, Norma B. Romero, Robert J. Bryson-Richardson, Baziel G.M. van Engelen, Nicol C. Voermans, Coen A.C. Ottenheijm

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Figure 2

TMS to study in vivo muscle-relaxation kinetics.

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TMS to study in vivo muscle-relaxation kinetics. (A) Schematic of the ex...
(A) Schematic of the experimental setup for TMS to induce involuntary muscle relaxation (top). Typical, superimposed, force traces, and corresponding electromyogram (EMG) of a control subject (CTRL) and NEM6 patient during maximal voluntary contraction and TMS-induced involuntary relaxation of the deep-finger flexors (middle and bottom). Note the motor-evoked potential on the EMG traces corresponding to the small superimposed twitch and the EMG silent period of approximately 200 ms corresponding to the drop in force, after which voluntary force is generated again. Note the slower relaxation in the NEM6 patient. (B) Maximal force is lower in NEM6 patients than in controls, both in males and in females. (C) The peak relaxation rate (normalized to maximal force; pRR) is lower in NEM6 patients than in controls. (D) The time to 75% of maximal force (0.75 relaxation time) is longer in NEM6 patients than in controls. Orange circle corresponds to the NEM6 patient harboring the KBTBD13K390N mutation, white circles to those with the KBTBD13R408C mutation. Student’s t tests were performed between NEM6 and controls. *P < 0.05. For detailed information on the number of samples and statistical tests and outcomes, please see Supplemental Table 1.