KBTBD13 is an actin-binding protein that modulates muscle kinetics

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

doi:10.1172/JCI124000

KBTBD13 is an actin-binding protein that modulates muscle kinetics

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. JohnsonFrank 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

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

30 Scopus citations

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 GFPlabeled 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.

Original language	English
Pages (from-to)	754-767
Number of pages	14
Journal	Journal of Clinical Investigation
Volume	130
Issue number	2
DOIs	https://doi.org/10.1172/JCI124000
State	Published - Feb 3 2020

Bibliographical note

Publisher Copyright:
© 2020, American Society for Clinical Investigation.

Funding

This work was supported by the Dutch Foundation for Scientific Research (VIDI 016.126.319 to CACO); the Princess Beatrix Muscle Foundation (W.OR17-08 to CACO, NCV, and BGMVE); H2020-MSCA-RISE-2014 (645648 Muscle Stress Relief to CACO); the Advanced Photon Source (DE-AC02-06CH11357); A Foundation Building Strength for Nemaline Myopathy (to CACO); the National Health and Medical Research Council (NHMRC) Early Career Fellowship (APP1121651 to MY); the National Institute of Child Health and Human Development (NIH R01 HD075802 to AHB); the Muscular Dystrophy Association (USA) (MDA602235 to AHB); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH R01 AR053897 to HG), the NIH (HL133359 to KC). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. This project was supported by grant 9 P41 GM103622 from the National Institute of General Medical Sciences of the NIH. Use of the Pilatus 3 1M detector was provided by grant 1S10OD018090-01 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute of General Medical Sciences or the NIH. MP was funded by a postdoctoral grant from the Swedish Research Council (2015-00385).

Funders	Funder number
Dutch Foundation for Scientific Research	VIDI 016.126.319
NCV	645648, H2020-MSCA-RISE-2014
Princess Beatrix Muscle Foundation	W.OR17-08
National Institutes of Health (NIH)	R01 HD075802
National Institutes of Health (NIH)
U.S. Department of Energy EPSCoR
National Heart, Lung, and Blood Institute (NHLBI)	U01HL133359
National Heart, Lung, and Blood Institute (NHLBI)
National Institute of General Medical Sciences	1S10OD018090-01
National Institute of General Medical Sciences
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R01 AR053897
National Institute of Arthritis and Musculoskeletal and Skin Diseases
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research
Muscular Dystrophy Association	MDA602235
Muscular Dystrophy Association
Office of Science Programs
Argonne National Laboratory	9 P41 GM103622
Argonne National Laboratory
Advanced Photon Sciences	DE-AC02-06CH11357
Advanced Photon Sciences
Australian National Health and Medical Research Council	APP1121651
Australian National Health and Medical Research Council
Vetenskapsrådet	2015-00385
Vetenskapsrådet

ASJC Scopus subject areas

General Medicine

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10.1172/JCI124000

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De Winter, J. M., Molenaar, J. P., Yuen, M., Van Der Pijl, R., Shen, S., Conijn, S., Van De Locht, M., Willigenburg, M., Bogaards, S. J. P., Van Kleef, E. S. B., Lassche, S., Persson, M., Rassier, D. E., Sztal, T. E., Ruparelia, A. A., Oorschot, V., Ramm, G., Hall, T. E., Xiong, Z., ... Ottenheijm, C. A. C. (2020). KBTBD13 is an actin-binding protein that modulates muscle kinetics. Journal of Clinical Investigation, 130(2), 754-767. https://doi.org/10.1172/JCI124000

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title = "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 GFPlabeled 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.",

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

note = "Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",

year = "2020",

month = feb,

day = "3",

doi = "10.1172/JCI124000",

language = "English",

volume = "130",

pages = "754--767",

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De Winter, JM, Molenaar, JP, Yuen, M, Van Der Pijl, R, Shen, S, Conijn, S, Van De Locht, M, Willigenburg, M, Bogaards, SJP, Van Kleef, ESB, Lassche, S, Persson, M, Rassier, DE, Sztal, TE, Ruparelia, AA, Oorschot, V, Ramm, G, Hall, TE, Xiong, Z, Johnson, CN, Li, F, Kiss, B, Lozano-Vidal, N, Boon, RA, Marabita, M, Nogara, L, Blaauw, B, Rodenburg, RJ, Küsters, B, Doorduin, J, Beggs, AH, Granzier, H, Campbell, K, Ma, W, Irving, T, Malfatti, E, Romero, NB, Bryson-Richardson, RJ, Van Engelen, BGM, Voermans, NC & Ottenheijm, CAC 2020, 'KBTBD13 is an actin-binding protein that modulates muscle kinetics', Journal of Clinical Investigation, vol. 130, no. 2, pp. 754-767. https://doi.org/10.1172/JCI124000

TY - JOUR

T1 - KBTBD13 is an actin-binding protein that modulates muscle kinetics

AU - De Winter, Josine M.

AU - Molenaar, Joery P.

AU - Yuen, Michaela

AU - Van Der Pijl, Robbert

AU - Shen, Shengyi

AU - Conijn, Stefan

AU - Van De Locht, Martijn

AU - Willigenburg, Menne

AU - Bogaards, Sylvia J.P.

AU - Van Kleef, Esmee S.B.

AU - Lassche, Saskia

AU - Persson, Malin

AU - Rassier, Dilson E.

AU - Sztal, Tamar E.

AU - Ruparelia, Avnika A.

AU - Oorschot, Viola

AU - Ramm, Georg

AU - Hall, Thomas E.

AU - Xiong, Zherui

AU - Johnson, Christopher N.

AU - Li, Frank

AU - Kiss, Balazs

AU - Lozano-Vidal, Noelia

AU - Boon, Reinier A.

AU - Marabita, Manuela

AU - Nogara, Leonardo

AU - Blaauw, Bert

AU - Rodenburg, Richard J.

AU - Küsters, Benno

AU - Doorduin, Jonne

AU - Beggs, Alan H.

AU - Granzier, Henk

AU - Campbell, Ken

AU - Ma, Weikang

AU - Irving, Thomas

AU - Malfatti, Edoardo

AU - Romero, Norma B.

AU - Bryson-Richardson, Robert J.

AU - Van Engelen, Baziel G.M.

AU - Voermans, Nicol C.

AU - Ottenheijm, Coen A.C.

PY - 2020/2/3

Y1 - 2020/2/3

N2 - 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 GFPlabeled 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.

AB - 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 GFPlabeled 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.

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JO - Journal of Clinical Investigation

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KBTBD13 is an actin-binding protein that modulates muscle kinetics

Abstract

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