TY - JOUR
T1 - Muscle ankyrin repeat protein 1 (MARP1) locks titin to the sarcomeric thin filament and is a passive force regulator
AU - van der Pijl, Robbert J.
AU - van den Berg, Marloes
AU - van de Locht, Martijn
AU - Shen, Shengyi
AU - Bogaards, Sylvia J. P.
AU - Conijn, Stefan
AU - Langlais, Paul
AU - Hooijman, Pleuni E.
AU - Labeit, Siegfried
AU - Heunks, Leo M. A.
AU - Granzier, Henk
AU - Ottenheijm, Coen A. C.
N1 - Funding Information: Olaf S. Andersen served as editor. The authors thank the research nurses, intensivists, and surgeons of the VU Medical Center, Netherlands Cancer Institute? Antoni van Leeuwenhoek, and Medisch Spectrum Twente who were involved with patient inclusion and biopsies. The authors thank Dr. Stephan Lange and Dr. Ju Chen (School of Medicine, University of California, San Diego, San Diego, CA) for providing the MARP1-3 triple KO mice. Research reported in this work was supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant R01HL121500 (to C.A.C. Ottenheijm), Marie Sk?odowska-Curie Research and Innovation Staff Exchange 2014 project 645648 (Muscle Stress Relief; to C.A.C. Ottenheijm and S. Labeit), National Institutes of Health/National Heart, Lung, and Blood Institute grant R35HL144998 (to H. Granzier), and National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR073179 (to H. Granzier). Funding Information: Research reported in this work was supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant R01HL121500 (to C.A.C. Ottenheijm), Marie Skłodowska-Curie Research and Innovation Staff Exchange 2014 project 645648 (Muscle Stress Relief; to C.A.C. Ottenheijm and S. Labeit), National Institutes of Health/National Heart, Lung, and Blood Institute grant R35HL144998 (to H. Granzier), and National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR073179 (to H. Granzier). The authors declare no competing financial interests. Publisher Copyright: © 2021 van der Pijl et al. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7/5
Y1 - 2021/7/5
N2 - Muscle ankyrin repeat protein 1 (MARP1) is frequently up-regulated in stressed muscle, but its effect on skeletal muscle function is poorly understood. Here, we focused on its interaction with the titin-N2A element, found in titin's molecular spring region. We show that MARP1 binds to F-actin, and that this interaction is stronger when MARP1 forms a complex with titin-N2A. Mechanics and super-resolution microscopy revealed that MARP1 "locks" titin-N2A to the sarcomeric thin filament, causing increased extension of titin's elastic PEVK element and, importantly, increased passive force. In support of this mechanism, removal of thin filaments abolished the effect of MARP1 on passive force. The clinical relevance of this mechanism was established in diaphragm myofibers of mechanically ventilated rats and of critically ill patients. Thus, MARP1 regulates passive force by locking titin to the thin filament. We propose that in stressed muscle, this mechanism protects the sarcomere from mechanical damage.
AB - Muscle ankyrin repeat protein 1 (MARP1) is frequently up-regulated in stressed muscle, but its effect on skeletal muscle function is poorly understood. Here, we focused on its interaction with the titin-N2A element, found in titin's molecular spring region. We show that MARP1 binds to F-actin, and that this interaction is stronger when MARP1 forms a complex with titin-N2A. Mechanics and super-resolution microscopy revealed that MARP1 "locks" titin-N2A to the sarcomeric thin filament, causing increased extension of titin's elastic PEVK element and, importantly, increased passive force. In support of this mechanism, removal of thin filaments abolished the effect of MARP1 on passive force. The clinical relevance of this mechanism was established in diaphragm myofibers of mechanically ventilated rats and of critically ill patients. Thus, MARP1 regulates passive force by locking titin to the thin filament. We propose that in stressed muscle, this mechanism protects the sarcomere from mechanical damage.
UR - http://www.scopus.com/inward/record.url?scp=85109115237&partnerID=8YFLogxK
U2 - https://doi.org/10.1085/jgp.202112925
DO - https://doi.org/10.1085/jgp.202112925
M3 - Article
C2 - 34152365
SN - 0022-1295
VL - 153
JO - The Journal of general physiology
JF - The Journal of general physiology
IS - 7
M1 - e202112925
ER -