A Novel Three-Filament Model of Force Generation in Eccentric Contraction of Skeletal Muscles

Schappacher‐Tilp, Gudrun; Leonard, Tim; Desch, Gertrud; Herzog, Walter

doi:10.1371/journal.pone.0117634

Cited by 89 publications

(85 citation statements)

References 49 publications

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“…A binding location was later predicted at N2A, limiting titin's extendible spring length to include only its stiffest PEVK and distal Ig segments . A mathematical model predicting N2A binding to the thin filament underestimated experimental values of titin force enhancement (Powers et al, 2014;Schappacher-Tilp et al, 2015). Thus, PEVK must become stiffer (beyond the effects of Ca 2+ and beyond the effects of N2A binding) in an actively stretched sarcomere to explain experimental observations of titin force enhancement.…”

Section: Discussionmentioning

confidence: 98%

“…It has been suggested that titin force enhancement could occur if titin binds to the thin filament to shorten and stiffen its available spring length during active sarcomere stretch (Herzog, 2014;Nishikawa et al, 2012;Powers et al, 2014). Conceptually, titin binding to the thin filaments provides a mechanism that can account for large, rapid and reversible force enhancement in actively stretched sarcomeres (Schappacher-Tilp et al, 2015). Therefore, if this hypothetical titin binding could be prevented, actively stretched sarcomeres would be more compliant (Fig.…”

Section: +mentioning

confidence: 99%

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Decreased force enhancement in skeletal muscle sarcomeres with a deletion in titin

Powers

Nishikawa

Joumaa

et al. 2016

Journal of Experimental Biology

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In the cross-bridge theory, contractile force is produced by crossbridges that form between actin and myosin filaments. However, when a contracting muscle is stretched, its active force vastly exceeds the force that can be attributed to cross-bridges. This unexplained, enhanced force has been thought to originate in the giant protein titin, which becomes stiffer in actively compared with passively stretched sarcomeres by an unknown mechanism. We investigated this mechanism using a genetic mutation (mdm) with a small but crucial deletion in the titin protein. Myofibrils from normal and mdm mice were stretched from sarcomere lengths of 2.5 to 6.0 μm. Actively stretched myofibrils from normal mice were stiffer and generated more force than passively stretched myofibrils at all sarcomere lengths. No increase in stiffness and just a small increase in force were observed in actively compared with passively stretched mdm myofibrils. These results are in agreement with the idea that titin force enhancement stiffens and stabilizes the sarcomere during contraction and that this mechanism is lost with the mdm mutation.

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Section: Discussionmentioning

confidence: 98%

Section: +mentioning

confidence: 99%

Decreased force enhancement in skeletal muscle sarcomeres with a deletion in titin

Powers

Nishikawa

Joumaa

et al. 2016

Journal of Experimental Biology

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“…This increase in force from steady-state passive to active states beyond filament overlap is inferred to come from modulation of titin-based force by a mechanism not yet understood. Current speculation is that titin force is modulated when the titin protein becomes shorter and stiffer upon activation Leonard and Herzog, 2010;Nishikawa et al, 2012;Schappacher-Tilp et al, 2015). Previous studies in myofibrils from mdm mice show that, with a deletion in the titin protein, titin force enhancement and contractile force are substantially decreased (e.g.…”

Section: Discussionmentioning

confidence: 99%

Titin force enhancement following active stretch of skinned skeletal muscle fibres

Powers

Joumaa

Jinha

et al. 2017

Journal of Experimental Biology

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In actively stretched skeletal muscle sarcomeres, titin-based force is enhanced, increasing the stiffness of active sarcomeres. Titin force enhancement in sarcomeres is vastly reduced in mdm, a genetic mutation with a deletion in titin. Whether loss of titin force enhancement is associated with compensatory mechanisms at higher structural levels of organization, such as single fibres or entire muscles, is unclear. The aim of this study was to determine whether mechanical deficiencies in titin force enhancement are also observed at the fibre level, and whether mechanisms compensate for the loss of titin force enhancement. Single skinned fibres from control and mutant mice were stretched actively and passively beyond filament overlap to observe titin-based force. Mutant fibres generated lower contractile stress (force divided by cross-sectional area) than control fibres. Titin force enhancement was observed in control fibres stretched beyond filament overlap, but was overshadowed in mutant fibres by an abundance of collagen and high variability in mechanics. However, titin force enhancement could be measured in all control fibres and most mutant fibres following short stretches, accounting for ∼25% of the total stress following active stretch. Our results show that the partial loss of titin force enhancement in myofibrils is not preserved in all mutant fibres and this mutation likely affects fibres differentially within a muscle. An increase in collagen helps to reestablish total force at long sarcomere lengths with the loss in titin force enhancement in some mutant fibres, increasing the overall strength of mutant fibres.

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“…player in explaining the differences between predictions and experiments [14 -17], there is still debate and an incomplete understanding with regard to the underlying force-producing mechanisms [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

The active force–length relationship is invisible during extensive eccentric contractions in skinned skeletal muscle fibres

et al. 2017

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In contrast to experimentally observed progressive forces in eccentric contractions, cross-bridge and sliding-filament theories of muscle contraction predict that varying myofilament overlap will lead to increases and decreases in active force during eccentric contractions. Non-cross-bridge contributions potentially explain the progressive total forces. However, it is not clear whether underlying abrupt changes in the slope of the nonlinear forcelength relationship are visible in long isokinetic stretches, and in which proportion cross-bridges and non-cross-bridges contribute to muscle force. Here, we show that maximally activated single skinned rat muscle fibres behave (almost across the entire working range) like linear springs. The force slope is about three times the maximum isometric force per optimal length. Cross-bridge and non-cross-bridge contributions to the muscle force were investigated using an actomyosin inhibitor. The experiments revealed a nonlinear progressive contribution of non-cross-bridge forces and suggest a nonlinear cross-bridge contribution similar to the active force-length relationship (though with increased optimal length and maximum isometric force). The linear muscle behaviour might significantly reduce the control effort. Moreover, the observed slight increase in slope with initial length is in accordance with current models attributing the non-cross-bridge force to titin.

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A Novel Three-Filament Model of Force Generation in Eccentric Contraction of Skeletal Muscles

Cited by 89 publications

References 49 publications

Decreased force enhancement in skeletal muscle sarcomeres with a deletion in titin

Decreased force enhancement in skeletal muscle sarcomeres with a deletion in titin

Titin force enhancement following active stretch of skinned skeletal muscle fibres

The active force–length relationship is invisible during extensive eccentric contractions in skinned skeletal muscle fibres

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