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It has been speculated that binding of MARP1 to the N2A element alters titin’s stiffness ( Miller et al., 2003 Zhou et al., 2016).
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These sequences unfold sequentially, starting with the PEVK segment and followed by the tandem Ig repeats at longer sarcomere lengths (reviewed in Granzier and Labeit, 2004). At the N2A elements distal end is the PEVK segment (proline, glutamate, valine, lysine-rich) that extends greatly and dominates titin’s elasticity in intermediate to long sarcomeres ( Trombitás et al., 1998a, Trombitás et al., 1998b). The N2A element is flanked at its proximal end by a tandem Ig segment (tandemly arranged Ig-like domains) that can change length and generate force by unbending of interdomain linker sequences. Additionally, missense mutations in the N2A-Us have been linked to cardiomyopathy ( Arimura et al., 2009 Akinrinade et al., 2019), thereby also supporting a critical role of N2A-Us in cardiac health. The importance of the N2A element to muscle health is supported by a mouse model with a spontaneous mutation, resulting in an in-frame deletion of part of I82/I83 in the N2A element (the mdm model) that develops severe myopathy with early death ( Garvey et al., 2002 Witt et al., 2004). The N2A element of titin contains four Ig domains and several unique sequences, of which the 104-residue unique sequence (N2A-Us, the sequence to which MARP1 binds) with flanking Ig domains I80 and I81 is a major component ( Labeit and Kolmerer, 1995). MARP1 is known to interact with several sarcomere proteins and primarily with the N2A element of titin ( Miller et al., 2003 Zhou et al., 2016), found within titin’s extensible region that spans from near the sarcomere’s Z-disc to near the end of the thick filaments. MARP1 is of interest as in skeletal muscle it is normally present at very low levels, but its level increases markedly under conditions of mechanical stress ( Barash et al., 2004 Witt et al., 2004 Wette et al., 2017 van der Pijl et al., 2018). Here, we focus on a muscle ankyrin repeat protein 1 (MARP1), also known as Ankrd1/CARP (reviewed in Ling et al., 2017 van der Pijl et al., 2019). Many proteins are known to interact with the sarcomeric filaments and tune their functional properties ( Granzier and Labeit, 2005). We propose that in stressed muscle, this mechanism protects the sarcomere from mechanical damage. Thus, MARP1 regulates passive force by locking titin to the thin filament. The clinical relevance of this mechanism was established in diaphragm myofibers of mechanically ventilated rats and of critically ill patients. In support of this mechanism, removal of thin filaments abolished the effect of MARP1 on passive force. 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. We show that MARP1 binds to F-actin, and that this interaction is stronger when MARP1 forms a complex with titin–N2A. Here, we focused on its interaction with the titin–N2A element, found in titin’s molecular spring region. Muscle ankyrin repeat protein 1 (MARP1) is frequently up-regulated in stressed muscle, but its effect on skeletal muscle function is poorly understood.