Maximal ATPase Activity and Calcium Sensitivity of Reconstituted Myofilaments are Unaltered by the Fetal Troponin T Re-expressed During Human Heart Failure

Torrealba, José; Lozano, Emilio Gerzaín Manzo; Griffin, Michael; Stoker, Scott W.; McDonald, Kerry S.; Greaser, Marion L.; Wolff, Matthew R.

doi:10.1006/jmcc.2002.2016

Cited by 7 publications

(6 citation statements)

References 32 publications

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“…A similar switch in cTnT isoform expression has been observed in myocardium from failing human hearts, where there is a reexpression of the fetal isoform, cTnT 4 , and a downregulation in normal adult cTnT 3 (3,4). Again, it remains unclear as to the exact functional consequences of these changes in cTnT isoform content, although it appears that expression of the fetal isoform of cTnT does not alter either maximal Ca 2ϩ -activated ATPase activity or calcium sensitivity in reconstituted myofilaments (40). It is known, however, that varied expression of cTnT isoforms correlates with Ca 2ϩ sensitivity of isometric force in skinned cardiac muscle (32).…”

Section: Discussionmentioning

confidence: 75%

Exercise improves impaired ventricular function and alterations of cardiac myofibrillar proteins in diabetic dyslipidemic pigs

Korte¹,

Mokelke²,

Sturek

et al. 2005

Journal of Applied Physiology

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. Exercise improves impaired ventricular function and alterations of cardiac myofibrillar proteins in diabetic dyslipidemic pigs. J Appl Physiol 98: [461][462][463][464][465][466][467] 2005. First published October 1, 2004; doi:10.1152/japplphysiol.00551.2004.-Chronic diabetes is often associated with cardiomyopathy, which may result, in part, from defects in cardiac muscle proteins. We investigated whether a 20-wk porcine model of diabetic dyslipidemia (DD) would impair in vivo myocardial function and yield alterations in cardiac myofibrillar proteins and whether endurance exercise training would improve these changes. Myocardial function was depressed in anesthetized DD pigs (n ϭ 12) compared with sedentary controls (C; n ϭ 13) as evidenced by an ϳ30% decrease in left ventricular fractional shortening and an ϳ35% decrease in ϩdP/dt measured by noninvasive echocardiography and direct cardiac catheterization, respectively. This depression in myocardial function was improved with chronic exercise as treadmill-trained DD pigs (DDX) (n ϭ 13) had significantly greater fractional shortening and ϩdP/dt than DD animals. Interestingly, the isoform expression pattern of the myofibrillar regulatory protein, cardiac troponin T (cTnT), was significantly shifted from cTnT1 toward cTnT2 and cTnT3 in DD pigs. Furthermore, this change in cTnT isoform expression pattern was prevented in DDX pigs. Finally, there was a decrease in baseline levels of cAMPdependent protein kinase-induced phosphorylation of the myofibrillar proteins troponin I and myosin-binding protein-C in DD animals. Overall, these results indicate that 20 wk of DD lead to myocardial dysfunction coincident with significant alterations in myofibrillar proteins, both of which are prevented with endurance exercise training, implying that changes in myofibrillar proteins may contribute, at least in part, to cardiac dysfunction associated with diabetic cardiomyopathy.cardiomyopathy; diabetes mellitus; lipids; myocardium DIABETES MELLITUS IS A DISEASE with wide prevalence in humans and is often associated with cardiovascular complications that represent the major cause of morbidity and mortality. Patients with diabetes have a high incidence of congestive heart failure, which may occur independent of coronary artery atherosclerosis, valvular heart disease, and hypertension (23). This deterioration of heart function is known as diabetic cardiomyopathy and is frequently associated with both systolic and diastolic left ventricular dysfunction (36). Much of what is known about the features of myocardial dysfunction has been obtained using rat models of diabetes. Rats treated with streptozotocin (STZ) develop diabetes mellitus associated with hypoinsulinemia, hyperglycemia, polyuria, weight loss, and myocardial dysfunction. The contractile dysfunction is due in part to contractile abnormalities of the myocyte, which are present within 4 days of diabetes (37). Myocytes isolated from diabetic rat hearts exhibit much slower contraction and relaxation rates (37). These contracti...

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Section: Discussionmentioning

confidence: 75%

Exercise improves impaired ventricular function and alterations of cardiac myofibrillar proteins in diabetic dyslipidemic pigs

Korte¹,

Mokelke²,

Sturek

et al. 2005

Journal of Applied Physiology

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“…5), is now known to be an important modulator of thin filament function. Thin filament properties and actin-myosin interactions can be affected by troponin tail changes that are either isoform switches (32,58,59), missense mutations (14 -18, 21-23), or truncations (60 -62). In a recent report (26), we showed that bovine cardiac troponin tail peptide TnT-(1-156) suppresses thin filamentmyosin S1 ATPase activity, weakens myosin S1-thin filament binding, and affects tropomyosin-binding position on actin.…”

Section: Discussionmentioning

confidence: 99%

Folding and Function of the Troponin Tail Domain

Hinkle

Tobacman

2003

Journal of Biological Chemistry

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Troponin contains a globular Ca 2؉ -binding domain and an elongated tail domain composed of the N terminus of subunit troponin T (TnT). The tail domain anchors troponin to tropomyosin and actin, modulates myosin function, and is a site of cardiomyopathy-inducing mutations. Critical interactions between tropomyosin and troponin are proposed to depend on tail domain residues 112-136, which are highly conserved across phyla. Most cardiomyopathy mutations in TnT flank this region. Three such mutations were examined and had contrasting effects on peptide TnT-(1-156), promoting folding and thermal stability assessed by circular dichroism (F110I) or weakening folding and stability (T104V and to a small extent R92Q). Folding of both TnT-(1-156) and whole troponin was promoted by replacing bovine TnT Thr-104 with human TnT Ala-104, further indicating the importance of this cardiomyopathy site residue for protein folding. Mutation F110I markedly stabilized the troponin tail but weakened binding of holo-troponin to actin-tropomyosin 8-fold, suggesting that loss of flexibility impairs troponin tail function. The effect of the F110I mutation on troponintropomyosin binding to actin was much less, indicating this flexibility is particularly important for the interactions of troponin with tropomyosin. We suggest that most cardiomyopathic mutations in the troponin tail alter muscle function indirectly, by perturbing interactions between troponin and tropomyosin requisite for the complex effects of these proteins on myosin.In striated muscles, including the heart and skeletal muscle, contraction is tightly regulated by the reversible binding of Ca 2ϩ to the thin filament protein troponin. Tight and specific attachment of troponin to the thin filament is mediated by the troponin tail domain, which is composed of the N-terminal portion of TnT 1 and interacts with the tropomyosin C terminus. Hydrodynamic studies (1), rotary-shadowed electron micrographs of troponin (2), and intermediate resolution studies of both troponin-tropomyosin (3) and TnT-tropomyosin co-crystals (4) indicate that the tail domain is highly asymmetric and ϳ160 Å in length. Electron microscopy of tropomyosin-TnT co-crystals suggests that a long region of the tropomyosin C terminus may interact with the troponin tail (4). However, most of this extended interaction may be very weak, because a variety of other evidence suggests that only the C terminus of tropomyosin binds strongly to troponin (reviewed in Ref. 5). Recently, an x-ray crystallographic study of the tropomyosin C terminus identified and determined the structure of an 18-residue tropomyosin region that comprises a critical TnT-binding site (6). The TnT element that binds to this tropomyosin region is unknown.A new approach to these important interactions has been provided by the discovery that any of several mutations in the troponin tail region can cause the autosomal dominant disorder, familial hypertrophic cardiomyopathy (FHC). Regardless whether because of mutations in thick filament or thin filame...

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“…Previous studies of the functional effects of the cTnT isoforms have used proteins in solution, reconstituted myofilaments, and cells in culture (17,43,49,52,54). Calciumactivated ATPase activity did not differ between myofilaments reconstituted with human TnT (hcTnT) cTnT 3 or hcTnT 4 (52) and hcTnT 1 , hcTnT 2 , hcTnT 3 , or hcTnT 4 (17), but calcium sensitivity of S 1 -ATPase activity was less in the presence of the longer bovine cTnT isoform than the shorter isoform (50).…”

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confidence: 99%

cTnT₁, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform

Nassar

Malouf²,

Rockman³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Four isoforms of cardiac troponin T (cTnT), a protein essential for calcium-dependent myocardial force development, are expressed in the human; they differ in charge and length. Their expression is regulated developmentally and is affected by disease states. Human cTnT (hcTnT) isoform effects have been examined in reconstituted myofilaments. In this study, we evaluated the modulatory effects of overexpressing one cTnT isoform on in vitro and in vivo myocardial function. A hcTnT isoform, hcTnT(1), expressed during development and in heart disease but not in the normal adult heart, was expressed in transgenic (TG) mice (1-30% of total cTnT). Maximal active tension measured in skinned myocardium decreased as a function of relative hcTnT(1) expression. The pCa at half-maximal force development, Hill coefficient, and rate of redevelopment of force did not change significantly with hcTnT(1) expression. In vivo maximum rates of rise and fall of left ventricular pressure decreased, and the half-time of isovolumic relaxation increased, with hcTnT(1) expression. Substituting total cTnT charge for hcTnT(1) expression resulted in similar conclusions. Morphometric analysis and electron microscopy revealed no differences between wild-type (non-TG) and TG myocardium. No differences in isoform expression of tropomyosin, myosin heavy chain, essential and regulatory myosin light chains (MLC), TnI, or in posttranslational modifications of mouse cTnT, cTnI, or regulatory MLC were observed. These results support the hypothesis that cTnT isoform amino-terminal differences affect myofilament function and suggest that hcTnT(1) expression levels present during human development and in human heart disease can affect in vivo ventricular function.

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Maximal ATPase Activity and Calcium Sensitivity of Reconstituted Myofilaments are Unaltered by the Fetal Troponin T Re-expressed During Human Heart Failure

Cited by 7 publications

References 32 publications

Exercise improves impaired ventricular function and alterations of cardiac myofibrillar proteins in diabetic dyslipidemic pigs

Exercise improves impaired ventricular function and alterations of cardiac myofibrillar proteins in diabetic dyslipidemic pigs

Folding and Function of the Troponin Tail Domain

cTnT₁, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform

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Maximal ATPase Activity and Calcium Sensitivity of Reconstituted Myofilaments are Unaltered by the Fetal Troponin T Re-expressed During Human Heart Failure

Cited by 7 publications

References 32 publications

Exercise improves impaired ventricular function and alterations of cardiac myofibrillar proteins in diabetic dyslipidemic pigs

Exercise improves impaired ventricular function and alterations of cardiac myofibrillar proteins in diabetic dyslipidemic pigs

Folding and Function of the Troponin Tail Domain

cTnT1, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform

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Product

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cTnT₁, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform