Expression of slow skeletal troponin I in adult transgenic mouse heart muscle reduces the force decline observed during acidic conditions

Wolska, Beata M.; Vijayan, Kalpana; Arteaga, Grace M.; Konhilas, John P.; Phillips, R. M.; Kim, Robert; Naya, Taihei; Leiden, Jeffrey M.; Martin, Anne F.; Tombe, Pieter P. de; Solaro, R. John

doi:10.1111/j.1469-7793.2001.00863.x

Cited by 69 publications

(49 citation statements)

References 48 publications

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“…10 It has also been shown that the expression of slow skeletal troponin I in the heart of adult transgenic mice reduced the force decline observed under acidic conditions. 26 Another study showed that depressed troponin I protein phosphorylation was associated with the functional characteristics of a failing heart. 27 Those studies suggest that the sequential activation and expression of different isoforms of a contractile gene family might be the one of mechanisms of regulating contractile properties in the heart under various pathologic conditions.…”

Section: Discussionmentioning

confidence: 99%

Re-Expression of Fetal Troponin Isoforms in the Postinfarction Failing Heart of the Rat.

Kim

Kim²,

Lee³

2002

Circ J

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Section: Discussionmentioning

confidence: 99%

Re-Expression of Fetal Troponin Isoforms in the Postinfarction Failing Heart of the Rat.

Kim

Kim²,

Lee³

2002

Circ J

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“…All transgenic TnT mice had approximately 50% of their endogenous TnT protein replaced with either WT or mutant human cardiac TnT (19,24). Expression of ssTNI (25) increased the pCa 50 to a similar extent as expression of TnT-I79N at baseline, and pCa 50 increased to an even higher extent after protein kinase A phosphorylation ( Figure 1B).…”

Section: Increased Incidence Of Ventricular Arrhythmias In Mice Exprementioning

confidence: 92%

Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice

Baudenbacher¹,

Schober²,

Pinto³

et al. 2008

J. Clin. Invest.

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177

235

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In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca 2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing ventricular tachycardia was directly proportional to the degree of Ca 2+ sensitization caused by the troponin T mutation. Arrhythmia susceptibility was reproduced with the Ca 2+ -sensitizing agent EMD 57033 and prevented by myofilament Ca 2+ desensitization with blebbistatin. Ca 2+ sensitization markedly changed the shape of ventricular action potentials, resulting in shorter effective refractory periods, greater beat-to-beat variability of action potential durations, and increased dispersion of ventricular conduction velocities at fast heart rates. Together these effects created an arrhythmogenic substrate. Thus, myofilament Ca 2+ sensitization represents a heretofore unrecognized arrhythmia mechanism. The protective effect of blebbistatin provides what we believe to be the first direct evidence that reduction of Ca 2+ sensitivity in myofilaments is antiarrhythmic and might be beneficial to individuals with hypertrophic cardiomyopathy.

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“…We chose the slow skeletal isoform for these studies inasmuch as it is naturally expressed in the embryonic/neonatal period. Hearts of TG-ssTnI mice had slower relaxation kinetics, depressed effects of β-adrenergic stimulation [8], and protection against acidosis [9,10] and ischemia/reperfusion injury [11]. All of these properties are properties of preparations from neonatal rat hearts, and indicated that the special cardiac function in the neonatal period is importantly controlled by the isoform of TnI.…”

Section: Specific Modifications In Troponin I Affect the Dynamics Andmentioning

confidence: 99%

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

Solaro

Rosevear

Kobayashi

2008

Biochemical and Biophysical Research Communications

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105

119

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We review development of evidence and current perceptions of the multiple and significant functions of cardiac troponin I in regulation and modulation of cardiac function. Our emphasis is on the unique structure function relations of the cardiac isoform of troponin I, especially regions containing sites of phosphorylation. The data indicate that modifications of specific regions cardiac troponin I by phosphorylations either promote or reduce cardiac contractility. Thus, a homeostatic balance in these phosphorylations is an important aspect of control of cardiac function. A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I. KeywordsCardiac; Sarcomeres; Adrenergic stimulation; Mechanics; Kinases; Phosphatases In the time since the troponin discovery and naming by the laboratory of Setsuro Ebashi [1], there has been a constant stream of evidence indicating the substantial role of modifications in cardiac troponin (cTn) as a critical control element in the body's response to physiological stressors such as the hemodynamic demands of exercise. It is now widely recognized that regulatory processes at the level of the sarcomeres and the hetero-trimeric Tn complex involve not only the reception of Ca 2+ by cTnC, but also transduction of this Ca-binding signal by cTnI and cTnT [2,3]. Multiple interactions of cTnI and cTnT with actin and tropomyosin (Tm) control the number and kinetics of interactions of cross-bridges with the thin filament. Our focus here on cTnI serves to highlight the significant impact of modifications in the function of Tn in working cardiac myocytes and in the integrated physiological responses to exercise, which we have reviewed previously [4,5]. Evidence summarized below indicates that phosphorylation of cTnI by adrenergic signaling cascades is an indispensable control mechanism in matching cardiac output to venous return and myocyte dynamics to heart rate. Specific modifications in troponin I affect the dynamics and intensity of the heart beatElucidation of the function of an N-terminal extension of ~30 amino acids with sites (Ser-23, Ser-24) of phosphorylation by protein kinase A (PKA), not present in the fast skeletal (fsTnI) or slow skeletal isoforms (ssTnI), provided the first evidence that cTnI may have a special role * Corresponding

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Expression of slow skeletal troponin I in adult transgenic mouse heart muscle reduces the force decline observed during acidic conditions

Cited by 69 publications

References 48 publications

Re-Expression of Fetal Troponin Isoforms in the Postinfarction Failing Heart of the Rat.

Re-Expression of Fetal Troponin Isoforms in the Postinfarction Failing Heart of the Rat.

Myofilament Ca2+ sensitization causes susceptibility to cardiac arrhythmia in mice

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

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