Titin visualization in real time reveals an unexpected level of mobility within and between sarcomeres

Lopes, Katharina da Silva; Pietas, Agnieszka; Radkë, Michaël; Gotthardt, Michael

doi:10.1085/jgp1376oia4

Cited by 15 publications

(24 citation statements)

References 65 publications

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“…However, this was not associated with an elevated active force. Although an inhomogeneous distribution of wild-type and N2B-deficient titin could also result in a lower active force, it is unlikely that titins expressed from different alleles distribute non-uniformly among sarcomeres because, in a recent study, we always observed a homogeneous distribution of GFP-tagged titin versus non-tagged titin in heterozygous animals from different alleles (da Silva Lopes et al, 2011). However, even a homogeneous distribution of wild-type and N2B-deficient titin would not stabilize the filament lattice as expected from the increase in passive stiffness, because the unequal tensile forces that WT-WT titin double strands exert compared with those of WT-KO and KO-KO strands on a thick filament would shift the position of the thick filament from the center of the surrounding hexagonal array of the thin filaments.…”

Section: Modulation Of Force Development Kinetics By Titinmentioning

confidence: 84%

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Elhamine

Radkë

Pfitzer

et al. 2014

Journal of Cell Science

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Cardiac titin is the main determinant of sarcomere stiffness during diastolic relaxation. To explore whether titin stiffness affects the kinetics of cardiac myofibrillar contraction and relaxation, we used subcellular myofibrils from the left ventricles of homozygous and heterozygous N2B-knockout mice which express truncated cardiac titins lacking the unique elastic N2B region. Compared with myofibrils from wild-type mice, myofibrils from knockout and heterozygous mice exhibit increased passive myofibrillar stiffness. To determine the kinetics of Ca 2+ -induced force development (rate constant k ACT ), myofibrils from knockout, heterozygous and wildtype mice were stretched to the same sarcomere length (2.3 mm) and rapidly activated with Ca 2+. Additionally, mechanically induced force-redevelopment kinetics (rate constant k TR ) were determined by slackening and re-stretching myofibrils during Ca 2+ -mediated activation. Myofibrils from knockout mice exhibited significantly higher k ACT , k TR and maximum Ca 2+ -activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca 2+ ] were not significantly different among the three genotypes. These results indicate that increased titin stiffness promotes myocardial contraction by accelerating the formation of force-generating crossbridges without decelerating relaxation.

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Section: Modulation Of Force Development Kinetics By Titinmentioning

confidence: 84%

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Elhamine

Radkë

Pfitzer

et al. 2014

Journal of Cell Science

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“…To assess this, we imaged EGFP-labeled M-band striations using AM from knockin mice that express a C-terminally tagged titin-EGFP fusion protein (38). We found a significant transversal latency difference between peripheral and central M-band deformations during sarcomere shortening in live AMs under baseline conditions ( Figure 7C; compare Supplemental Videos 1 and 2 or Supplemental Videos 3 and 4).…”

Section: Discussionmentioning

confidence: 97%

Axial tubule junctions control rapid calcium signaling in atria

Brandenburg¹,

Kohl²,

Williams³

et al. 2016

Journal of Clinical Investigation

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187

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“…Here, we demonstrate that the Xin-aciculin complex, as revealed by BiFC, is localized at FLNc-containing sites during EPS-induced muscle remodeling and seems to be involved in myofibril repair. FRAP of unstimulated myotubes revealed extremely high dynamics and mobility of aciculin compared to other sarcomeric proteins (da Silva Lopes et al, 2011;Hartman et al, 2009;Wang et al, 2005;Wang et al, 2011), both at Z-discs and premyofibrils. Application of EPS even further increased aciculin dynamics (Fig.…”

Section: Functional Implications Of Aciculin-containing Protein Complmentioning

confidence: 94%

Aciculin interacts with filamin C and Xin and is essential for myofibril assembly, remodeling and maintenance

Molt

Bührdel

Yakovlev

et al. 2014

Journal of Cell Science

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Filamin C (FLNc) and Xin actin-binding repeat-containing proteins (XIRPs) are multi-adapter proteins mainly expressed in cardiac and skeletal muscles that play important roles in the assembly and repair of myofibrils and their attachment to the membrane. We identified the dystrophin-binding protein aciculin (PGM5), as a novel interaction partner of FLNc and Xin. All three proteins colocalize at intercalated discs of cardiac muscle and myotendinous junctions of skeletal muscle, while FLNc and aciculin also colocalize in mature Z-discs. Bimolecular fluorescence complementation experiments in developing cultured mammalian skeletal muscle cells demonstrate that Xin and aciculin also interact in FLNc-containing immature myofibrils and areas of myofibrillar remodeling and repair induced by electrical pulse stimulation (EPS). FRAP experiments show that aciculin is a highly dynamic and mobile protein. Aciculin knockdown in myotubes leads to failure in myofibril assembly, alignment and membrane attachment, and massive reduction in myofibril number. A highly similar phenotype was found upon depletion of aciculin in zebrafish embryos. Our results point to a thus far unappreciated but essential function of aciculin in myofibril formation, maintenance and remodeling.

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Titin visualization in real time reveals an unexpected level of mobility within and between sarcomeres

Cited by 15 publications

References 65 publications

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Deletion of the titin N2B region accelerates myofibrillar force development but does not alter relaxation kinetics

Axial tubule junctions control rapid calcium signaling in atria

Aciculin interacts with filamin C and Xin and is essential for myofibril assembly, remodeling and maintenance

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