Titin as a force-generating muscle protein under regulatory control

Freundt, Johanna K.; Linke, Wolfgang A.

doi:10.1152/japplphysiol.00865.2018

Cited by 107 publications

(89 citation statements)

References 97 publications

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“…Furthermore, there is extensive evidence that the semi-active protein titin ( Maruyama et al, 1976 ) mediates the phenomena of enhanced force response during and following stretch contractions [(r)FE] in skeletal muscle ( Tomalka et al, 2017 ; Herzog, 2018 ; Freundt and Linke, 2019 ). Various model approaches ( Rode et al, 2009 ; Nishikawa et al, 2012 ; Schappacher-Tilp et al, 2015 ) have been proposed that explain rFE in skeletal muscle and these model approaches are supported by experimental evidence for titin-actin interactions upon muscle activation ( Nagy, 2004 ; Bianco et al, 2007 ; Dutta et al, 2018 ; Li et al, 2018 ; Tahir et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Cross-Bridges and Sarcomeric Non-cross-bridge Structures Contribute to Increased Work in Stretch-Shortening Cycles

et al. 2020

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Stretch-shortening cycles (SSCs) refer to the muscle action when an active muscle stretch is immediately followed by active muscle shortening. This combination of eccentric and concentric contractions is the most important type of daily muscle action and plays a significant role in natural locomotion such as walking, running or jumping. SSCs are used in human and animal movements especially when a high movement speed or economy is required. A key feature of SSCs is the increase in muscular force and work during the concentric phase of a SSC by more than 50% compared with concentric muscle actions without prior stretch (SSC-effect). This improved muscle capability is related to various mechanisms, including pre-activation, stretch-reflex responses and elastic recoil from serial elastic tissues. Moreover, it is assumed that a significant contribution to enhanced muscle capability lies in the sarcomeres itself. Thus, we investigated the force output and work produced by single skinned fibers of rat soleus muscles during and after ramp contractions at a constant velocity. Shortening, lengthening, and SSCs were performed under physiological boundary conditions with 85% of the maximum shortening velocity and stretch-shortening magnitudes of 18% of the optimum muscle length. The different contributions of cross-bridge (XB) and non-cross-bridge (non-XB) structures to the total muscle force were identified by using Blebbistatin. The experiments revealed three main results: (i) partial detachment of XBs during the eccentric phase of a SSC, (ii) significantly enhanced forces and mechanical work during the concentric phase of SSCs compared with shortening contractions with and without XB-inhibition, and (iii) no residual force depression after SSCs. The results obtained by administering Blebbistatin propose a titin-actin interaction that depends on XB-binding or active XB-based force production. The findings of this study further suggest that enhanced forces generated during the active lengthening phase of SSCs persist during the subsequent shortening phase, thereby contributing to enhanced

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Section: Introductionmentioning

confidence: 99%

Cross-Bridges and Sarcomeric Non-cross-bridge Structures Contribute to Increased Work in Stretch-Shortening Cycles

et al. 2020

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“…Therefore, alterations in titin‐based spring force affect both the passive and the active forces of cardiomyocytes. The modulation of titin spring force can occur via two principal mechanisms, the switch of titin isoforms and post‐translational modifications (PTMs), although additional mechanisms (e.g., binding of Ca 2+ or chaperones) also play a role .…”

Section: Introductionmentioning

confidence: 99%

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Koser¹,

Loescher²,

Linke³

2019

The FEBS Journal

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Titin is a giant elastic protein expressed in the contractile units of striated muscle cells, including the sarcomeres of cardiomyocytes. The last decade has seen enormous progress in our understanding of how titin molecular elasticity is modulated in a dynamic manner to help cardiac sarcomeres adjust to the varying hemodynamic demands on the heart. Crucial events mediating the rapid modulation of cardiac titin stiffness are post‐translational modifications (PTMs) of titin. In this review, we first recollect what is known from earlier and recent work on the molecular mechanisms of titin extensibility and force generation. The main goal then is to provide a comprehensive overview of current insight into the relationship between titin PTMs and cardiomyocyte stiffness, notably the effect of oxidation and phosphorylation of titin spring segments on titin stiffness. A synopsis is given of which type of oxidative titin modification can cause which effect on titin stiffness. A large part of the review then covers the mechanically relevant phosphorylation sites in titin, their location along the elastic segment, and the protein kinases and phosphatases known to target these sites. We also include a detailed coverage of the complex changes in phosphorylation at specific titin residues, which have been reported in both animal models of heart disease and in human heart failure, and their correlation with titin‐based stiffness alterations. Knowledge of the relationship between titin PTMs and titin elasticity can be exploited in the search for therapeutic approaches aimed at softening the pathologically stiffened myocardium in heart failure patients.

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“…It is proposed that rTE occurs due to a stiffening and shortening of titin's free spring length in the presence of calcium and cross-bridge cycling [27], effectively increasing the contribution of passive force to total force following active lengthening. Therefore, while matching torque, the increase in passive tension associated with rTE [5,30] requires less muscle activation as compared with a purely ISO contraction [28,29]. This activation reduction is regularly measured through a decrease in electromyography (EMG) and has been observed in both submaximally and maximally activated contractions [3,7,28,31].…”

Section: Introductionmentioning

confidence: 99%

The Inhibitory Tendon-Evoked Reflex Is Increased in the Torque-Enhanced State Following Active Lengthening Compared to a Purely Isometric Contraction

2019

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Residual torque enhancement (rTE) is a history-dependent property of muscle, which results in an increase in steady-state isometric torque production following an active lengthening contraction as compared to a purely isometric (ISO) contraction at the same muscle length and level of activation. Once thought to be only an intrinsic property of muscle, recent evidence during voluntary contractions indicates a neuromechanical coupling between motor neuron excitability and the contractile state of the muscle. However, the mechanism by which this occurs has yet to be elucidated. The purpose of this study was to investigate inhibition arising from tendon-mediated feedback (e.g., Golgi tendon organ; GTO) through tendon electrical stimulation (TStim) in the ISO and rTE states during activation-matching and torque-matching tasks. Fourteen male participants (22 ± 2 years) performed 10 activation-matching contractions at 40% of their maximum tibialis anterior electromyography amplitude (5 ISO/5 rTE) and 10 torque-matching contractions at 40% of their maximum dorsiflexion torque (5 ISO/5 rTE). During both tasks, 10 TStim were delivered during the isometric steady state of all contractions, and the resulting tendon-evoked inhibitory reflexes were averaged and analyzed. Reflex amplitude increased by ~23% in the rTE state compared to the ISO state for the activation-matching task, and no differences were detected for the torque-matching task. The current data indicate an important relationship between afferent feedback in the torque-enhanced state and voluntary control of submaximal contractions. The history-dependent properties of muscle is likely to alter motor neuron excitability through modifications in tension- or torque-mediated afferent feedback arising from the tendon.

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Titin as a force-generating muscle protein under regulatory control

Cited by 107 publications

References 97 publications

Cross-Bridges and Sarcomeric Non-cross-bridge Structures Contribute to Increased Work in Stretch-Shortening Cycles

Cross-Bridges and Sarcomeric Non-cross-bridge Structures Contribute to Increased Work in Stretch-Shortening Cycles

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

The Inhibitory Tendon-Evoked Reflex Is Increased in the Torque-Enhanced State Following Active Lengthening Compared to a Purely Isometric Contraction

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