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 - Publisher Copyright:
© 2021 van der Pijl et al.
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.
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U2 - 10.1085/jgp.202112925
DO - 10.1085/jgp.202112925
M3 - Article
C2 - 34152365
AN - SCOPUS:85109115237
SN - 0022-1295
VL - 153
JO - Journal of General Physiology
JF - Journal of General Physiology
IS - 7
M1 - e202112925
ER -