A molecular map of titin/connectin elasticity reveals two different mechanisms acting in series

Gautel, Mathias; Goulding, David

doi:10.1016/0014-5793(96)00338-9

Cited by 108 publications

(83 citation statements)

References 17 publications

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“…Titin's elastic I-band region is composed of two serially linked spring elements: tandem immunoglobulin (Ig) domains and the PEVK segment (Gautel and Goulding, 1996). At relatively short sarcomere lengths, passive stretch straightens the folded tandem Ig domains with little change in tension.…”

Section: Titin Structure and Functionmentioning

confidence: 99%

Eccentric contraction: unraveling mechanisms of force enhancement and energy conservation

Nishikawa

2016

Journal of Experimental Biology

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During the past century, physiologists have made steady progress in elucidating the molecular mechanisms of muscle contraction. However, this progress has so far failed to definitively explain the high force and low energy cost of eccentric muscle contraction. Hypotheses that have been proposed to explain increased muscle force during active stretch include cross-bridge mechanisms, sarcomere and half-sarcomere length non-uniformity, and engagement of a structural element upon muscle activation. The available evidence suggests that force enhancement results from an interaction between an elastic element in muscle sarcomeres, which is engaged upon activation, and the cross-bridges, which interact with the elastic elements to regulate their length and stiffness. Similarities between titin-based residual force enhancement in vertebrate muscle and twitchin-based 'catch' in invertebrate muscle suggest evolutionary homology. The winding filament hypothesis suggests plausible molecular mechanisms for effects of both Ca 2+ influx and crossbridge cycling on titin in active muscle. This hypothesis proposes that the N2A region of titin binds to actin upon Ca 2+ influx, and that the PEVK region of titin winds on the thin filaments during force development because the cross-bridges not only translate but also rotate the thin filaments. Simulations demonstrate that a muscle model based on the winding filament hypothesis can predict residual force enhancement on the descending limb of the length-tension curve in muscles during eccentric contraction. A kinematic model of titin winding based on sarcomere geometry makes testable predictions about titin isoforms in different muscles. Ongoing research is aimed at testing these predictions and elucidating the biochemistry of the underlying protein interactions.

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Section: Titin Structure and Functionmentioning

confidence: 99%

Eccentric contraction: unraveling mechanisms of force enhancement and energy conservation

Nishikawa

2016

Journal of Experimental Biology

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“…At the longer sarcomere lengths, force increases steeply because the PEVK region elongates as a Hookean spring (Linke et al, 1998). The steep increase in passive force starts at different sarcomere lengths in muscles (Wang et al, 1991;Gautel and Goulding, 1996) with different titin isoforms and with PEVK segments of different size.…”

Section: Titin Structure and Functionmentioning

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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“…In the I-band, titin is composed of proximal and distal tandem Ig segments that flank the PEVK region. The proximal tandem Ig and PEVK segments function as springs in series [14,26]. In the Z-disc, titin is anchored to thin filaments, a-actinin, and anti-parallel titin molecules from the adjacent sarcomere [27].…”

Section: Layout Of Titin Within Muscle Sarcomeresmentioning

confidence: 99%

“…At shorter sarcomere lengths, passive stretch straightens the folded Ig domains of I-band titin with little increase in passive tension [28,29]. At longer sarcomere lengths, the PEVK domain elongates and the passive tension increases steeply [26,30]. PEVK behaves as an entropic spring at low force, but as an enthalpic, or Hookean, spring at higher forces [14,31].…”

Section: Titin Contributes To Muscle Passive Tensionmentioning

confidence: 99%

Is titin a ‘winding filament’? A new twist on muscle contraction

et al. 2011

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Recent studies have demonstrated a role for the elastic protein titin in active muscle, but the mechanisms by which titin plays this role remain to be elucidated. In active muscle, Ca 2þ -binding has been shown to increase titin stiffness, but the observed increase is too small to explain the increased stiffness of parallel elastic elements upon muscle activation. We propose a 'winding filament' mechanism for titin's role in active muscle. First, we hypothesize that Ca 2þ -dependent binding of titin's N2A region to thin filaments increases titin stiffness by preventing low-force straightening of proximal immunoglobulin domains that occurs during passive stretch. This mechanism explains the difference in length dependence of force between skeletal myofibrils and cardiac myocytes. Second, we hypothesize that cross-bridges serve not only as motors that pull thin filaments towards the M-line, but also as rotors that wind titin on the thin filaments, storing elastic potential energy in PEVK during force development and active stretch. Energy stored during force development can be recovered during active shortening. The winding filament hypothesis accounts for force enhancement during stretch and force depression during shortening, and provides testable predictions that will encourage new directions for research on mechanisms of muscle contraction.

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A molecular map of titin/connectin elasticity reveals two different mechanisms acting in series

Cited by 108 publications

References 17 publications

Eccentric contraction: unraveling mechanisms of force enhancement and energy conservation

Eccentric contraction: unraveling mechanisms of force enhancement and energy conservation

Non-crossbridge stiffness in active muscle fibres

Is titin a ‘winding filament’? A new twist on muscle contraction

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