Effect of different troponin T-tropomyosin combinations on thin filament activation

Schachat, Fred; Diamond, Michael S.; Brandt, Philip W.

doi:10.1016/0022-2836(87)90300-7

Cited by 155 publications

(94 citation statements)

References 22 publications

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“…Our previous report showed that cTnT isoforms modulated the Ca 2ϩ sensitivity of force development and the ability of Tn to inhibit actomyosin ATPase activity (4). Other laboratories (5,6,9,27,28) have also shown a correlation between TnT isoforms and Ca 2ϩ sensitivity of force development. Significant advances in the understanding of the functional significance of the developmental transition from the ssTnI to cTnI isoform expression in cardiac myocytes have been obtained over the last 5 years.…”

Section: ϫ015) Than Intact Fibers Similar To What Has Been Reported mentioning

confidence: 84%

Cardiac Troponin T Isoforms Affect the Ca2+ Sensitivity of Force Development in the Presence of Slow Skeletal Troponin I

Gomes¹,

Venkatraman

Davis

et al. 2004

Journal of Biological Chemistry

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In this study we investigated the physiological role of the cardiac troponin T (cTnT) isoforms in the presence of human slow skeletal troponin I (ssTnI). ssTnI is the main troponin I isoform in the fetal human heart. In reconstituted fibers containing the cTnT isoforms in the presence of ssTnI, cTnT1-containing fibers showed increased Ca 2؉ sensitivity of force development compared with cTnT3-and cTnT4-containing fibers. The maximal force in reconstituted skinned fibers was significantly greater for the cTnT1 (predominant fetal cTnT isoform) when compared with cTnT3 (adult TnT isoform) in the presence of ssTnI. Troponin (Tn) complexes containing ssTnI and reconstituted with cTnT isoforms all yielded different maximal actomyosin ATPase activities. Tn complexes containing cTnT1 and cTnT4 (both fetal isoforms) had a reduced ability to inhibit actomyosin ATPase activity when compared with cTnT3 (adult isoform) in the presence of ssTnI. The rate at which Ca 2؉ was released from site II of cTnC in the cTnI⅐cTnC complex (122/s) was 12.5-fold faster than for the ssTnI⅐cTnC complex (9.8/s). Addition of cTnT3 to the cTnI⅐cTnC complex resulted in a 3.6-fold decrease in the Ca 2؉ dissociation rate from site II of cTnC. Addition of cTnT3 to the ssTnI⅐cTnC complex resulted in a 1.9-fold increase in the Ca 2؉ dissociation rate from site II of cTnC. The rate at which Ca 2؉ dissociated from site II of cTnC in Tn complexes also depended on the cTnT isoform present. However, the TnI isoforms had greater effects on the Ca 2؉ dissociation rate of site II than the cTnT isoforms. These results suggest that the different N-terminal TnT isoforms would produce distinct functional properties in the presence of ssTnI when compared with cTnI and that each isoform would have a specific physiological role in cardiac muscle.

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Section: ϫ015) Than Intact Fibers Similar To What Has Been Reported mentioning

confidence: 84%

Cardiac Troponin T Isoforms Affect the Ca2+ Sensitivity of Force Development in the Presence of Slow Skeletal Troponin I

Gomes¹,

Venkatraman

Davis

et al. 2004

Journal of Biological Chemistry

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“…On Ca 2ϩ binding to TnC, a Ca 2ϩ -induced interaction of TnC with TnI relieves the inhibitory action of TnI exerted on the thin filament and enables the myosin head to cyclically interact with actin in the thin filament and generate force. The Ca 2ϩ sensitivity of muscle contraction is determined by the Ca 2ϩ -binding affinity of TnC, which is dynamically altered through interaction with TnI and TnT in the myofilament lattice (3)(4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

Ca ²⁺ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

Morimoto

Harada

et al. 2002

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

150

114

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A deletion mutation ⌬K210 in cardiac troponin T (cTnT) was recently found to cause familial dilated cardiomyopathy (DCM). To explore the effect of this mutation on cardiac muscle contraction under physiological conditions, we determined the Ca 2؉ -activated force generation in permeabilized rabbit cardiac muscle fibers into which the mutant and wild-type cTnTs were incorporated by using our TnT exchange technique. The free Ca 2؉ concentrations required for the force generation were higher in the mutant cTnTexchanged fibers than in the wild-type cTnT-exchanged ones, with no statistically significant differences in maximal force-generating capability and cooperativity. Exchanging the mutant cTnT into isolated cardiac myofibrils also increased the free Ca 2؉ concentrations required for the activation of ATPase. In contrast, a deletion mutation ⌬E160 in cTnT that causes familial hypertrophic cardiomyopathy (HCM) decreased the free Ca 2؉ concentrations required for force generation, just as in the case of the other HCM-causing mutations in cTnT. The results indicate that cTnT mutations found in the two distinct forms of cardiomyopathy (i.e., HCM and DCM) change the Ca 2؉ sensitivity of cardiac muscle contraction in opposite directions. The present study strongly suggests that Ca 2؉ desensitization of force generation in sarcomere is a primary mechanism for the pathogenesis of DCM associated with the deletion mutation ⌬K210 in cTnT.C ontraction of the vertebrate-striated muscles (i.e., skeletal and cardiac muscles) is regulated by Ca 2ϩ through its binding to a specific regulatory protein complex, troponin (Tn), which is distributed at regular intervals along the entire thin filament (1, 2). Tn is a complex of three different proteins, troponin T (TnT; tropomyosin-binding component), troponin I (TnI; inhibitory component), and troponin C (TnC; Ca 2ϩ -binding component). On Ca 2ϩ binding to TnC, a Ca 2ϩ -induced interaction of TnC with TnI relieves the inhibitory action of TnI exerted on the thin filament and enables the myosin head to cyclically interact with actin in the thin filament and generate force. The Ca 2ϩ sensitivity of muscle contraction is determined by the Ca 2ϩ -binding affinity of TnC, which is dynamically altered through interaction with TnI and TnT in the myofilament lattice (3-8).Mutations in genes for cardiac troponin T (cTnT) and cardiac troponin I (cTnI) have been found to cause familial hypertrophic cardiomyopathy (HCM), an autosomal dominant heart disease characterized by asymmetrical ventricular hypertrophy with a high incidence of sudden death in young adults (9). We have already examined the effects of eight HCM-linked cTnT mutations (I79N, R92Q, ⌬E160, E244D, R278C, and two truncated mutants produced by a splice donor site mutation Int15G 1 3A) and six HCM-linked cTnI mutations (R145G, R145Q, R162W, ⌬K183, G203S, and K206Q) on the contractile functions of cardiac muscle by using a technique for exchanging the exogenous Tn complex into skinned muscle fibers and isolated myofibrils. We found t...

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“…Modulating muscle power output appears to provide the ecologically important ability to operate at different points along a tradeoff between performance and energetic cost. S triated muscles from a variety of taxa show substantial interand intra-specific variation in the sensitivity of myosin crossbridge activation by calcium (1)(2)(3)(4)(5)(6). Within individual animals, calcium sensitivity of muscle activation varies during ontogeny, training, and disease and appears to be one of the primary ways that striated muscles adjust to changes in contractile regimes (7)(8)(9).…”

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confidence: 99%

“…Troponin T (TnT), one of the components of the troponin-tropomyosin complex, varies in isoform composition during development (14)(15)(16)(17), training (18), and human heart failure (19,20). Changes in TnT isoform composition frequently correlate with variation in the calcium sensitivity of myosin cross-bridge activation (1)(2)(3)(4)(5)(6)(7)(8)(9), and experimental manipulations of TnT isoform composition have been shown to affect the calcium sensitivity of actomyosin ATPase (21). Point mutations in human cardiac TnT alter both calcium sensitivity and myosin cross-bridge kinetics (22,23).…”

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confidence: 99%

Alternative splicing, muscle calcium sensitivity, and the modulation of dragonfly flight performance

Marden

Fitzhugh

Wolf

et al. 1999

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

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Calcium sensitivity of myosin cross-bridge activation in striated muscles commonly varies during ontogeny and in response to alterations in muscle usage, but the consequences for wholeorganism physiology are not well known. Here we show that the relative abundances of alternatively spliced transcripts of the calcium regulatory protein troponin T (TnT) vary widely in flight muscle of Libellula pulchella dragonflies, and that the mixture of TnT splice variants explains significant portions of the variation in muscle calcium sensitivity, wing-beat frequency, and an index of aerodynamic power output during free flight. Two size-distinguishable morphs differ in their maturational pattern of TnT splicing, yet they show the same relationship between TnT transcript mixture and calcium sensitivity and between calcium sensitivity and aerodynamic power output. This consistency of effect in different developmental and physiological contexts strengthens the hypothesis that TnT isoform variation modulates muscle calcium sensitivity and whole-organism locomotor performance. Modulating muscle power output appears to provide the ecologically important ability to operate at different points along a tradeoff between performance and energetic cost. S triated muscles from a variety of taxa show substantial interand intra-specific variation in the sensitivity of myosin crossbridge activation by calcium (1-6). Within individual animals, calcium sensitivity of muscle activation varies during ontogeny, training, and disease and appears to be one of the primary ways that striated muscles adjust to changes in contractile regimes (7-9). It generally is thought that varying the calcium sensitivity of muscle activation affects recruitment of force-generating cross-bridges during a calcium transient, thereby modulating the rate and amount of force and power output (7-12). However, little is presently known regarding the effects of variation in calcium sensitivity on whole-muscle contractile performance, locomotor ability, and energetics.Variation in muscle calcium sensitivity often involves changes in the molecular composition of the troponin-tropomyosin complex (7-9, 13). This group of molecules constitutes the molecular ''switch'' that turns myosin cross-bridge activity on and off in response to neurally induced calcium signals. Troponin T (TnT), one of the components of the troponin-tropomyosin complex, varies in isoform composition during development (14-17), training (18), and human heart failure (19,20). Changes in TnT isoform composition frequently correlate with variation in the calcium sensitivity of myosin cross-bridge activation (1-9), and experimental manipulations of TnT isoform composition have been shown to affect the calcium sensitivity of actomyosin ATPase (21). Point mutations in human cardiac TnT alter both calcium sensitivity and myosin cross-bridge kinetics (22,23). The emerging picture is that many regions of TnT interact in functionally significant ways with the other troponins, tropomyosin (7-9, 13), and perhaps with m...

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Effect of different troponin T-tropomyosin combinations on thin filament activation

Cited by 155 publications

References 22 publications

Cardiac Troponin T Isoforms Affect the Ca2+ Sensitivity of Force Development in the Presence of Slow Skeletal Troponin I

Cardiac Troponin T Isoforms Affect the Ca2+ Sensitivity of Force Development in the Presence of Slow Skeletal Troponin I

Ca ²⁺ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

Alternative splicing, muscle calcium sensitivity, and the modulation of dragonfly flight performance

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Effect of different troponin T-tropomyosin combinations on thin filament activation

Cited by 155 publications

References 22 publications

Cardiac Troponin T Isoforms Affect the Ca2+ Sensitivity of Force Development in the Presence of Slow Skeletal Troponin I

Cardiac Troponin T Isoforms Affect the Ca2+ Sensitivity of Force Development in the Presence of Slow Skeletal Troponin I

Ca 2+ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

Alternative splicing, muscle calcium sensitivity, and the modulation of dragonfly flight performance

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Ca ²⁺ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy