The N-Terminal Extension of Cardiac Troponin T Stabilizes the Blocked State of Cardiac Thin Filament

Gollapudi, Sampath K.; Mamidi, Ranganath; Mallampalli, Sri Lakshmi; Chandra, Murali

doi:10.1016/j.bpj.2012.07.035

Cited by 37 publications

(55 citation statements)

References 38 publications

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“…This is consistent with the observation of impaired Ca 2+ cooperative activation in muscle carrying cardiomyopathy-causing mutations in genes encoding cTnT (Manning et al 2011(Manning et al , 2012. Because tropomyosin overlap regions are required for proper formation of a ternary complex with the N-terminal tail of cTnT (Palm et al 2003) (which in turn is essential to maintain the thin filament in the B-state (Tobacman et al 2002;Gollapudi et al 2012)), this suggests that troponin mutations disrupt the structure of the troponintropomyosin complex (Sequeira et al 2015). Also, impaired tropomyosin-tropomyosin interactions could decrease nearneighbor interactions and decrease length-dependent activation.…”

Section: Cooperativity Of Length-dependent Activationsupporting

confidence: 72%

Historical perspective on heart function: the Frank–Starling Law

Sequeira

Velden

2015

Biophys Rev

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More than a century of research on the FrankStarling Law has significantly advanced our knowledge about the working heart. The Frank-Starling Law mandates that the heart is able to match cardiac ejection to the dynamic changes occurring in ventricular filling and thereby regulates ventricular contraction and ejection. Significant efforts have been attempted to identify a common fundamental basis for the Frank-Starling heart and, although a unifying idea has still to come forth, there is mounting evidence of a direct relationship between length changes in individual constituents (cardiomyocytes) and their sensitivity to Ca 2+ ions. As the Frank-Starling Law is a vital event for the healthy heart, it is of utmost importance to understand its mechanical basis in order to optimize and organize therapeutic strategies to rescue the failing human heart. The present review is a historic perspective on cardiac muscle function. We Brevive^a century of scientific research on the heart's fundamental protein constituents (contractile proteins), to their assemblies in the muscle (the sarcomeres), culminating in a thorough overview of the several synergistically events that compose the Frank-Starling mechanism. It is the authors' personal beliefs that much can be gained by understanding the Frank-Starling relationship at the cellular and whole organ level, so that we can finally, in this century, tackle the pathophysiologic mechanisms underlying heart failure.

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Section: Cooperativity Of Length-dependent Activationsupporting

confidence: 72%

Historical perspective on heart function: the Frank–Starling Law

Sequeira

Velden

2015

Biophys Rev

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“…1, in which a stretch of 1% of initial length was imposed on a muscle generating Ca 2ϩ -activated force that was ϳ25% maximal. The characteristic features of the stretch activation response have been elucidated in detail elsewhere (5,20,52). Briefly, following achievement of steady-state force generation, acute stretch elicits an immediate increase in force (P 1), due to distortion of attached cross bridges.…”

Section: Stretch Activation Experimentsmentioning

confidence: 99%

Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere

Cheng

Wan

McElfresh

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Mutations in cardiac myosin binding protein C (MyBP-C) are a common cause of familial hypertrophic cardiomyopathy (FHC). The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca²⁺ homeostasis, and in vivo cardiac function are unknown. To elucidate the effects of decreased MyBP-C expression on cardiac function, we employed MyBP-C heterozygous null (MyBP-C+/-) mice presenting decreases in MyBP-C expression (32%) similar to those of FHC patients carrying MyBP-C mutations. The levels of MyBP-C phosphorylation were reduced 53% in MyBP-C+/- hearts compared with wild-type hearts. Skinned myocardium isolated from MyBP-C+/- hearts displayed decreased cross-bridge stiffness at half-maximal Ca²⁺ activations, increased steady-state force generation, and accelerated rates of cross-bridge recruitment at low Ca²⁺ activations (<15% and <25% of maximum, respectively). Protein kinase A treatment abolished basal differences in rates of cross-bridge recruitment between MyBP-C+/- and wild-type myocardium. Intact ventricular myocytes from MyBP-C+/- hearts displayed abnormal sarcomere shortening but unchanged Ca²⁺ transient kinetics. Despite a lack of left ventricular hypertrophy, MyBP-C+/- hearts exhibited elevated end-diastolic pressure and decreased peak rate of LV pressure rise, which was normalized following dobutamine infusion. Furthermore, electrocardiogram recordings in conscious MyBP-C+/- mice revealed prolonged QRS and QT intervals, which are known risk factors for cardiac arrhythmia. Collectively, our data show that reduced MyBP-C expression and phosphorylation in the sarcomere result in myofilament dysfunction, contributing to contractile dysfunction that precedes compensatory adaptations in Ca²⁺ handling, and chamber remodeling. Perturbations in mechanical and electrical activity in MyBP-C+/- mice could increase their susceptibility to cardiac dysfunction and arrhythmia.

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“…thin filament in the B state (49,50), supporting that at least the current cTnT mutation may confer a greater availability of myosinbinding sites on actin. Altogether, these findings indicate that mutations in troponin proteins may disrupt the blockade of tropomyosin on actin, which precedes the rise of cytosolic Ca 2+ , and are able to augment actin-myosin interactions during the diastolic phase in HCM patients.…”

Section: Discussionmentioning

confidence: 77%

“…Normalized force-Ca 2+ relationships before and after protein kinase A (PKA) in the presence of ADP for MYH7 mut (A) and MYBPC3 mut (B) heart samples. Myofilament Ca 2+ sensitivity in the presence of ADP (EC 50 ) before (C) and after (D) PKA treatment in IDCM, HCM, and donor samples. Residual force, a measure of sarcomere stiffness, at high Ca 2+ with 100 μM ADP (EC 50 ) before (E) and after (F) PKA treatment in IDCM, HCM, and donor samples.…”

Section: Methodsmentioning

confidence: 99%

“…As shown in Fig. 2B, ADP sensitivity (denoted as EC 50 ) was higher in IDCM and several HCM patient groups, including MYH7 mut , TNNT2 mut , TNNI3 mut , and HCM smn , whereas it was lower in MYBPC3 mut (missense mutations) and MYBPC3 trunc (truncating mutations) compared with donors (Table S2). PKA normalized ADP sensitivity to donor levels in IDCM, MYH7 mut , and HCM smn , whereas TNNT2 mut and TNNI3 mut remained more sensitive to ADP (Fig.…”

mentioning

confidence: 87%

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ADP-stimulated contraction: A predictor of thin-filament activation in cardiac disease

Sequeira

Najafi

Wijnker

et al. 2015

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

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Diastolic dysfunction is general to all idiopathic dilated (IDCM) and hypertrophic cardiomyopathy (HCM) patients. Relaxation deficits may result from increased actin-myosin formation during diastole due to altered tropomyosin position, which blocks myosin binding to actin in the absence of Ca 2+ . We investigated whether ADP-stimulated force development (without Ca 2+ ) can be used to reveal changes in actin-myosin blockade in human cardiomyopathy cardiomyocytes. Cardiac samples from HCM patients, harboring thick-filament (MYH7 mut , MYBPC3 mut ) and thin-filament (TNNT2 mut , TNNI3 mut ) mutations, and IDCM were compared with sarcomere mutation-negative HCM (HCM smn ) and nonfailing donors. Myofilament ADP sensitivity was higher in IDCM and HCM compared with donors, whereas it was lower for MYBPC3. Increased ADP sensitivity in IDCM, HCM smn , and MYH7 mut was caused by low phosphorylation of myofilament proteins, as it was normalized to donors by protein kinase A (PKA) treatment. Troponin exchange experiments in a TNNT2 mut sample corrected the abnormal actin-myosin blockade. In MYBPC3 trunc samples, ADP sensitivity highly correlated with cardiac myosin-binding protein-C (cMyBP-C) protein level. Incubation of cardiomyocytes with cMyBP-C antibody against the actin-binding N-terminal region reduced ADP sensitivity, indicative of cMyBP-C's role in actin-myosin regulation. In the presence of Ca 2+ , ADP increased myofilament force development and sarcomere stiffness. Enhanced sarcomere stiffness in sarcomere mutation-positive HCM samples was irrespective of the phosphorylation background. In conclusion, ADP-stimulated contraction can be used as a tool to study how protein phosphorylation and mutant proteins alter accessibility of myosin binding on actin. In the presence of Ca 2+ , pathologic [ADP] and low PKA-phosphorylation, high actin-myosin formation could contribute to the impaired myocardial relaxation observed in cardiomyopathies.H eart failure (HF) is a syndrome clinically defined as the inability of the heart to sufficiently supply blood to organs and tissues (1). Systolic dysfunction is present in approximately one-half of the HF population, whereas diastolic dysfunction is a common feature in almost all HF patients (2). Moreover, in hypertrophic cardiomyopathy (HCM), which is caused by mutations in genes encoding thinand thick-filament proteins, impaired diastolic function is frequently observed (3). Impaired relaxation of the heart may be caused by high myofilament Ca 2+ sensitivity. This increased sensitivity for Ca 2+ would result in residual myofilament activation at diastolic [Ca 2+ ], which may delay the onset of ventricular relaxation and limit proper filling of the heart. High myofilament Ca 2+ sensitivity has been observed in both acquired and genetic forms of cardiomyopathy (3, 4). In human idiopathic dilated cardiomyopathy (IDCM), high myofilament Ca 2+ sensitivity has been associated with reduced β-adrenergic receptor-mediated phosphorylation by protein kinase A (PKA) (4). Reduced PKA phospho...

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The N-Terminal Extension of Cardiac Troponin T Stabilizes the Blocked State of Cardiac Thin Filament

Cited by 37 publications

References 38 publications

Historical perspective on heart function: the Frank–Starling Law

Historical perspective on heart function: the Frank–Starling Law

Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere

ADP-stimulated contraction: A predictor of thin-filament activation in cardiac disease

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