1. KBTBD13 is an actin-binding protein that modulates muscle kinetics
- Author
-
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, Malin, Rassier, D E, Sztal, T E, Ruparelia, A A, Oorschot, V, Ramm, G, Hall, T E, Xiong, Z, Johnson, C N, Li, F, Kiss, B, Lozano-Vidal, N, Boon, R A, Marabita, M, Nogara, L, Blaauw, B, Rodenburg, R J, Kusters, B, Doorduin, J, Beggs, A H, Granzier, H, Campbell, K, Ma, W, Irving, T, Malfatti, E, Romero, N B, Bryson-Richardson, R J, van Engelen, B G M, Voermans, N C, Ottenheijm, C A C, 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, Malin, Rassier, D E, Sztal, T E, Ruparelia, A A, Oorschot, V, Ramm, G, Hall, T E, Xiong, Z, Johnson, C N, Li, F, Kiss, B, Lozano-Vidal, N, Boon, R A, Marabita, M, Nogara, L, Blaauw, B, Rodenburg, R J, Kusters, B, Doorduin, J, Beggs, A H, Granzier, H, Campbell, K, Ma, W, Irving, T, Malfatti, E, Romero, N B, Bryson-Richardson, R J, van Engelen, B G M, Voermans, N C, and Ottenheijm, C A C
- 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 Kbtbd13(R408c)-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., Funding agencies:Dutch Foundation for Scientific Research VIDI 016.126.319Princess Beatrix Muscle Foundation W.OR17-08H2020-MSCA-RISE-2014 645648Advanced Photon Source DE-AC02-06CH11357Foundation Building Strength for Nemaline MyopathyNational Health and Medical Research Council (NHMRC) of Australia APP1121651 United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) NIH R01 HD075802 Muscular Dystrophy Association MDA602235 NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) NIH R01 AR053897 United States Department of Health & Human Services National Institutes of Health (NIH) - USA HL133359 United States Department of Energy (DOE) DE-AC02-06CH11357 NIH National Institute of General Medical Sciences (NIGMS)9 P41 GM103622 1S10OD018090-01
- Published
- 2020
- Full Text
- View/download PDF