Tuning Passive Mechanics through Differential Splicing of Titin during Skeletal Muscle Development

Ottenheijm, Coen A.C.; Knottnerus, Anna; Buck, Danielle; Luo, Xiuju; Greer, Kevin; Hoying, Adam; Labeit, Siegfried; Granzier, Henk

doi:10.1016/j.bpj.2009.07.041

Cited by 60 publications

(80 citation statements)

References 37 publications

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“…S1B). Our custom titin exon microarray (16) further validated only loss of expression of exons 251-269 in homozygous Ttn ΔIAjxn mice without adaptive changes in splicing elsewhere in titin (SI Appendix, Fig. S1C).…”

Section: Significancementioning

confidence: 88%

Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

Granzier

Hutchinson

Tonino

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Titin, the largest protein known, forms a giant filament in muscle where it spans the half sarcomere from Z disk to M band. Here we genetically targeted a stretch of 14 immunoglobulin-like and fibronectin type 3 domains that comprises the I-band/A-band (IA) junction and obtained a viable mouse model. Super-resolution optical microscopy (structured illumination microscopy, SIM) and electron microscopy were used to study the thick filament length and titin's molecular elasticity. SIM showed that the IA junction functionally belongs to the relatively stiff A-band region of titin. The stiffness of A-band titin was found to be high, relative to that of I-band titin (∼40-fold higher) but low, relative to that of the myosin-based thick filament (∼70-fold lower). Sarcomere stretch therefore results in movement of A-band titin with respect to the thick filament backbone, and this might constitute a novel lengthsensing mechanism. Findings disproved that titin at the IA junction is crucial for thick filament length control, settling a long-standing hypothesis. SIM also showed that deleting the IA junction moves the attachment point of titin's spring region away from the Z disk, increasing the strain on titin's molecular spring elements. Functional studies from the cellular to ex vivo and in vivo left ventricular chamber levels showed that this causes diastolic dysfunction and other symptoms of heart failure with preserved ejection fraction (HFpEF). Thus, our work supports titin's important roles in diastolic function and disease of the heart. passive stiffness | molecular elasticity | hypertrophy | mechanosensing

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Section: Significancementioning

confidence: 88%

Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

Granzier

Hutchinson

Tonino

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Skeletal muscle TTN length directly correlates with sarcomere elongation and muscle-type variation in elasticity [Wang et al, 1991]. This is related with postnatal variations in the I-band region, especially in PEVK [Freiburg et al, 2000;Trombitás et al, 2000;Ottenheijm et al, 2009], that lead to the shortening of TTN, thereby increasing skeletal muscle stiffness.…”

Section: Ttn Isoformsmentioning

confidence: 99%

A Rising Titan:TTNReview and Mutation Update

2014

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The 364 exon TTN gene encodes titin (TTN), the largest known protein, which plays key structural, developmental, mechanical, and regulatory roles in cardiac and skeletal muscles. Prior to next-generation sequencing (NGS), routine analysis of the whole TTN gene was impossible due to its giant size and complexity. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. In the last months, due to the widespread use of NGS, TTN is emerging as a major gene in human-inherited disease. So far, 127 TTN disease-causing mutations have been reported in patients with at least 10 different conditions, including isolated cardiomyopathies, purely skeletal muscle phenotypes, or infantile diseases affecting both types of striated muscles. However, the identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance, and correlation with the phenotype of TTN sequence changes. In this review, we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern, and phenotype-genotype correlations, alongside with their implications for basic research and for human health.

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“…In adulthood, titin is shorter and stiffer compared with soon after birth. The rearrangement is principally due to a reduction in the PEVK region length, suggesting that this leads to an increase in the calcium responsiveness of titin (Ottenheijm et al, 2009).…”

Section: Static Stiffness Dependence On Sarcomere Lengthmentioning

confidence: 99%

Non-crossbridge stiffness in active muscle fibres

Colombini

Nocella

Bagni

2016

Journal of Experimental Biology

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Stretching of an activated skeletal muscle induces a transient tension increase followed by a period during which the tension remains elevated well above the isometric level at an almost constant value. This excess of tension in response to stretching has been called 'static tension' and attributed to an increase in fibre stiffness above the resting value, named 'static stiffness'. This observation was originally made, by our group, in frog intact muscle fibres and has been confirmed more recently, by us, in mammalian intact fibres. Following stimulation, fibre stiffness starts to increase during the latent period well before crossbridge force generation and it is present throughout the whole contraction in both single twitches and tetani. Static stiffness is dependent on sarcomere length in a different way from crossbridge force and is independent of stretching amplitude and velocity. Static stiffness follows a time course which is distinct from that of active force and very similar to the myoplasmic calcium concentration time course. We therefore hypothesize that static stiffness is due to a calcium-dependent stiffening of a noncrossbridge sarcomere structure, such as the titin filament. According to this hypothesis, titin, in addition to its well-recognized role in determining the muscle passive tension, could have a role during muscle activity.

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Tuning Passive Mechanics through Differential Splicing of Titin during Skeletal Muscle Development

Cited by 60 publications

References 37 publications

Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

A Rising Titan:TTNReview and Mutation Update

Non-crossbridge stiffness in active muscle fibres

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