Assembly of the cardiac I-band region of titin/connectin: expression of the cardiac-specific regions and their structural relation to the elastic segments

Gautel, Mathias; Lehtonen, Eero; Pietruschka, F.

doi:10.1007/bf00123361

Cited by 37 publications

(24 citation statements)

References 41 publications

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“…Future research with antibodies that more precisely demarcate the proximal tandem Ig segment will be required to resolve this issue. It is clear from the present work, however, that Ig domain unfolding is, at best, of limited significance in explaining the large contour-length adjustment that takes place in titin at SLs 26 , with an antibody against I18 (mean I18 to edge of Z-disk distance shown in Figure 9 of Gautel et al 26 converted to T12 to I18 distance, by subtracting the 50-nm distance from the edge of Z-disk to T12 epitope 21 ).…”

Section: Does Contour-length Gain Results From Ig Domain Unfolding?contrasting

confidence: 55%

“…The obtained values indicate that this segment has a near zero length at SLs Ͻ2.2 m, whereas at longer SLs, it extends ( Figure 8C, Table). It is unlikely that this extension results from Ig domain unfolding (I18 and I19) because superimposing results with an antibody against I18 (from Gautel et al 26 ) with 9D10 data indicates that the distance between I18 and 9D10 does not increase with SL ( Figure 8C, compare open circles and closed black circles; see also legend to Figure 8). Instead, our findings provide evidence that the unique N2B sequence is extensible.…”

Section: Sequence Within Titin Underlying Contour-length Adjustmentmentioning

confidence: 96%

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Mechanically Driven Contour-Length Adjustment in Rat Cardiac Titin’s Unique N2B Sequence

Helmes

Trombitás

Centner

et al. 1999

Circulation Research

156

129

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Abstract-The giant elastic protein titin is largely responsible for passive forces in cardiac myocytes. A number of different titin isoforms with distinctly different structural elements within their central I-band region are expressed in human myocardium. Their coexpression has so far prevented an understanding of the respective contributions of the isoforms to myocardial elasticity. Using isoform-specific antibodies, we find in the present study that rat myocardium expresses predominantly the small N2B titin isoform, which allows us to characterize the elastic behavior of this isoform. The extensibility and force response of N2B titin were studied by using immunoelectron microscopy and by measuring the passive force-sarcomere length (SL) relation of single rat cardiac myocytes under a variety of mechanical conditions. Experimental results were compared with the predictions of a mechanical model in which the elastic titin segment behaves as two wormlike chains, the tandem immunoglobulin (Ig) segments and the PEVK segment (rich in proline, and lysine [K] residues), connected in series. The overall contour length was predicted from the sequence of N2B cardiac titin. According to mechanical measurements, above Ϸ2.2 m SL titin's elastic segment extends beyond its predicted contour length. Immunoelectron microscopy indicates that a prominent source of this contour-length gain is the extension of the unique N2B sequence (located between proximal tandem Ig segment and PEVK), and that Ig domain unfolding is negligible. Thus, the elastic region of N2B cardiac titin consists of three mechanically distinct extensible segments connected in series: the tandem Ig segment, the PEVK segment, and the unique N2B sequence. Rate-dependent and repetitive stretch-release experiments indicate that both the contour-length gain and the recovery from it involve kinetic processes, probably unfolding and refolding within the N2B segment. As a result, the contour length of titin's extensible segment depends on the rate and magnitude of the preceding mechanical perturbations. The rate of recovery from the length gain is slow, ensuring that the adjusted length is maintained through consecutive cardiac cycles and that hysteresis is minimal. Thus, as a result of the extensible properties of the unique N2B sequence, the I-band region of the N2B cardiac titin isoform functions as a molecular spring that is adjustable. (Circ Res. 1999;84:1339-1352.)Key Words: elasticity Ⅲ diastole Ⅲ myocardial compliance Ⅲ connectin Ⅲ passive force D uring diastole, while the ventricle fills, the myocardium is passively stretched. The rate of filling and the magnitude of the end-diastolic volume are significantly affected by the shape of the passive pressure-volume relation. Titin, a striated muscle-specific giant elastic protein, is largely responsible for the generation of the diastolic force in the cardiac myocyte. 1 In addition to influencing ventricular filling, titin also helps maintaining the structural integrity of the contracting sarcomere (for reviews, ...

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Section: Does Contour-length Gain Results From Ig Domain Unfolding?contrasting

confidence: 55%

Section: Sequence Within Titin Underlying Contour-length Adjustmentmentioning

confidence: 96%

Mechanically Driven Contour-Length Adjustment in Rat Cardiac Titin’s Unique N2B Sequence

Helmes

Trombitás

Centner

et al. 1999

Circulation Research

156

129

View full text Add to dashboard Cite

show abstract

“…Potential sources include unfolding of titin’s Ig domains and unfolding of secondary and tertiary structures contained in the large unique sequence in the N2B element of titin[36]. Although at physiological stretch rates unfolding of Ig domains is thought to require forces that exceed physiological levels[6–7, 9–10], the unfolding probability will be higher in the PEVK KO (due to its increased strain[15]). Thus, it is possible that Ig domain unfolding takes place in the KO and explains part of the remaining viscosity.…”

Section: Discussionmentioning

confidence: 99%

Titin based viscosity in ventricular physiology: An integrative investigation of PEVK–actin interactions

Chung

Methawasin

Nelson

et al. 2011

Journal of Molecular and Cellular Cardiology

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Viscosity is proposed to modulate diastolic function, but only limited understanding of the source(s) of viscosity exists. In-vitro experiments have shown that the proline-glutamic acid-valine-lysine (PEVK) rich element of titin interacts with actin, causing a viscous force in the sarcomere. It is unknown whether this mechanism contributes to viscosity in-vivo. We tested the hypothesis that PEVK-actin interaction causes cardiac viscosity and is important in-vivo via an integrative physiological study on a unique PEVK-knockout (KO) model. Both skinned cardiomyocytes and papillary muscle fibers were isolated from wildtype (WT) and PEVK KO mice and passive viscosity was examined using stretch-hold-release and sinusoidal analysis. Viscosity was reduced by ~60% in KO myocytes and ~50% in muscle fibers at room temperature. The PEVK-actin interaction was not modulated by temperature or diastolic calcium, but was increased by lattice compression. Stretch-hold and sinusoidal frequency protocols on intact isolated mouse hearts showed a smaller, 30–40% reduction in viscosity, possibly due to actomyosin interactions, and showed that microtubules did not contribute to viscosity. Transmitral Doppler echocardiography similarly revealed a 40% decrease in LV chamber viscosity in the PEVK KO in-vivo. This integrative study is the first to quantify the influence of a specific molecular (PEVK-actin) viscosity in-vivo and shows that PEVK-actin interactions are an important physiological source of viscosity.

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“…As discussed above, titin is the elastic component of the myofibril, maintaining the precise structural arrangement of thick and thin filaments and generating passive muscle stiffness. Alternative splicing of titin's PEVK region modifies the “spring” property, with shorter, stiffer versions typically found in the adult vertebrate heart [22,45,46,26]. Mutations affecting titin splicing that reduce passive stiffness are associated with dilated cardiomyopathy (DCM) and account for nearly one third of all cases of familial DCM [29].…”

Section: Alternative Splicing In Vertebrates and Its Impact On Musclementioning

confidence: 99%

Transcriptional regulation and alternative splicing cooperate in muscle fiber-type specification in flies and mammals

Spletter

Schnorrer

2014

Experimental Cell Research

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Muscles coordinate body movements throughout the animal kingdom. Each skeletal muscle is built of large, multi-nucleated cells, called myofibers, which are classified into several functionally distinct types. The typical fiber-type composition of each muscle arises during development, and in mammals is extensively adjusted in response to postnatal exercise. Understanding how functionally distinct muscle fiber-types arise is important for unraveling the molecular basis of diseases from cardiomyopathies to muscular dystrophies. In this review, we focus on recent advances in Drosophila and mammals in understanding how muscle fiber-type specification is controlled by the regulation of transcription and alternative splicing. We illustrate the cooperation of general myogenic transcription factors with muscle fiber-type specific transcriptional regulators as a basic principle for fiber-type specification, which is conserved from flies to mammals. We also examine how regulated alternative splicing of sarcomeric proteins in both flies and mammals can directly instruct the physiological and biophysical differences between fiber-types. Thus, research in Drosophila can provide important mechanistic insight into muscle fiber specification, which is relevant to homologous processes in mammals and to the pathology of muscle diseases.

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Assembly of the cardiac I-band region of titin/connectin: expression of the cardiac-specific regions and their structural relation to the elastic segments

Cited by 37 publications

References 41 publications

Mechanically Driven Contour-Length Adjustment in Rat Cardiac Titin’s Unique N2B Sequence

Mechanically Driven Contour-Length Adjustment in Rat Cardiac Titin’s Unique N2B Sequence

Titin based viscosity in ventricular physiology: An integrative investigation of PEVK–actin interactions

Transcriptional regulation and alternative splicing cooperate in muscle fiber-type specification in flies and mammals

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