Muscle Ankyrin Repeat Protein 1 (MARP1) Locks Titin to the Sarcomeric Thin Filament and is a Passive Force Regulator

Overview

Journal J Gen Physiol

Specialty Physiology

Date 2021 Jun 21

PMID 34152365

Citations 17

Authors

Robbert J Van der Pijl

Marloes Van Den Berg

Martijn van de Locht

Shengyi Shen

Sylvia J P Bogaards

Stefan Conijn

Paul Langlais

Pleuni E Hooijman

Siegfried Labeit

Leo M A Heunks

Henk Granzier

Coen A C Ottenheijm

Affiliations

Soon will be listed here.

Abstract

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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