Inorganic phosphate speeds loaded shortening in rat skinned cardiac myocytes

Hinken, Aaron C.; McDonald, Kerry S.

doi:10.1152/ajpcell.00049.2004

Cited by 34 publications

(53 citation statements)

References 40 publications

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“…It has been shown that in the presence of added P i force is depressed in cardiac muscle preparations (2,16,20). Consistent with the literature, Fig.…”

Section: Effect Of Tnc Mutations Onsupporting

confidence: 91%

Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities

Norman¹,

Rall²,

Tikunova³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Norman C, Rall JA, Tikunova SB, Davis JP. Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities. Am J Physiol Heart Circ Physiol 293: H2580-H2587, 2007. First published August 10, 2007; doi:10.1152/ajpheart.00039.2007.-We investigated whether changing thin filament Ca 2ϩ sensitivity alters the rate of contraction, either during normal cross-bridge cycling or when cross-bridge cycling is increased by inorganic phosphate (P i). We increased or decreased Ca 2ϩ sensitivity of force production by incorporating into rat skinned cardiac trabeculae the troponin C (TnC) mutants V44QTnCF27W and F20QTnCF27W . The rate of isometric contraction was assessed as the rate of force redevelopment (ktr) after a rapid release and restretch to the original length of the muscle. Both in the absence of added Pi and in the presence of 2.5 mM added Pi F27W . This study suggests that TnC Ca 2ϩ binding properties modulate the rate of cardiac muscle contraction at submaximal levels of Ca 2ϩ activation. This result has physiological relevance considering that, on a beat-to-beat basis, the heart contracts at submaximal Ca 2ϩ activation.force; thin filament CARDIAC MUSCLE CONTRACTION is initiated by Ca 2ϩ binding to troponin C (TnC), which triggers conformational changes on the thin filament, exposing myosin-binding sites on actin. After the myosin heads (cross bridges) attach to actin, the thin filaments slide along the thick filaments and the muscle contracts (18). The kinetics of cross-bridge cycling can be studied with several approaches. One approach has been developed by Brenner (3, 4). According to this protocol, a rapid shorteningrestretch maneuver mechanically detaches the cross bridges, and the rate at which the cross bridges reattach and generate force is a measure of the rate of contraction, known as the rate of force (tension) redevelopment (k tr ).In both cardiac and skeletal muscle, it is well established that k tr becomes faster with increasing levels of activation by Ca 2ϩ (5,6,13,28,46). Many studies have investigated the role Ca 2ϩ plays in the activation dependence of k tr (for review, see Ref. 13). It has been proposed that the effects of Ca 2ϩ on k tr occur either as a direct effect of Ca 2ϩ on the cross bridges or indirectly by activation of the thin filament, which subsequently allows cross bridges to cycle from non-force-generating states to force-generating states. Studies in skeletal muscle investigated the hypothesis that Ca 2ϩ has a direct effect on the cross bridge cycle. Caged inorganic phosphate (P i ) experiments suggest that Ca 2ϩ does not regulate the kinetics of P i release but rather the distribution of cross bridges between non-force-generating and force-generating states (25,45). Similarly, in vitro motility assays have shown that Ca 2ϩ , through binding to TnC, controls the number of cross bridges interacting with actin rather than directly controlling the rate of ATP hydrolysis or the filament sliding speed (14, 17). Moreover, Ca 2ϩ does...

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“…It has been shown that in the presence of added P i force is depressed in cardiac muscle preparations (2,16,20). Consistent with the literature, Fig.…”

Section: Effect Of Tnc Mutations Onsupporting

confidence: 91%

Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities

Norman¹,

Rall²,

Tikunova³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Measurement of force development kinetics was accomplished as previously described (16). In short, a cardiomyocyte in activating solution was allowed to develop steady-state force, after which it was rapidly slacked by 15-20% of the original cardiomyocyte length (L 0), held for 20 ms, and then rapidly restretched to a value slightly greater than L 0 for 2 ms before it was returned to L0.…”

Section: Methodsmentioning

confidence: 99%

“…Skinned myocyte preparation length traces, force-velocity curves, power-load curves, and rate constants of force redevelopment were analyzed as previously described (16,33). Frequency-dependent measurements of Ca 2ϩ transients and recovery rates were analyzed using repeated-measures ANOVA with Bonferroni post hoc analysis.…”

Section: Methodsmentioning

confidence: 99%

Elevated Ca²⁺transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Clay

Domeier

Hanft

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Clay SA, Domeier TL, Hanft LM, McDonald KS, Krenz M. Elevated Ca 2ϩ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines. Am J Physiol Heart Circ Physiol 308: H1086 -H1095, 2015. First published February 27, 2015 doi:10.1152/ajpheart.00501.2014.-Noonan syndrome with multiple lentigines (NSML) is primarily caused by mutations in the nonreceptor protein tyrosine phosphatase SHP2 and associated with congenital heart disease in the form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Our goal was to elucidate the cellular mechanisms underlying the development of HCM caused by the Q510E mutation in SHP2. NSML patients carrying this mutation suffer from a particularly severe form of HCM. Drawing parallels to other, more common forms of HCM, we hypothesized that altered Ca 2ϩ homeostasis and/or sarcomeric mechanical properties play key roles in the pathomechanism. We used transgenic mice with cardiomyocyte-specific expression of Q510E-SHP2 starting before birth. Mice develop neonatal onset HCM with increased ejection fraction and fractional shortening at 4 -6 wk of age. To assess Ca 2ϩ handling, isolated cardiomyocytes were loaded with fluo-4. Q510E-SHP2 expression increased Ca 2ϩ transient amplitudes during excitation-contraction coupling and increased sarcoplasmic reticulum Ca 2ϩ content concurrent with increased expression of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase. In skinned cardiomyocyte preparations from Q510E-SHP2 mice, force-velocity relationships and power-load curves were shifted upward. The peak power-generating capacity was increased approximately twofold. Transmission electron microscopy revealed that the relative intracellular area occupied by sarcomeres was increased in Q510E-SHP2 cardiomyocytes. Triton X-100-based myofiber purification showed that Q510E-SHP2 increased the amount of sarcomeric proteins assembled into myofibers. In summary, Q510E-SHP2 expression leads to enhanced contractile performance early in disease progression by augmenting intracellular Ca 2ϩ cycling and increasing the number of power-generating sarcomeres. This gives important new insights into the cellular pathomechanisms of Q510E-SHP2-associated HCM. contractility; sarcomeric function; sarco(endo)plasmic reticulum Ca 2ϩ -ATPase; cardiac hypertrophy; protein tyrosine phosphatase HYPERTROPHIC CARDIOMYOPATHY (HCM) affects ϳ1:500 adults (31) and represents one of the most common causes of sudden cardiac death in young individuals (49). Often the disease is detected in early adolescence, when patients develop arrhythmias, exercise intolerance, chest pain, or even sudden cardiac death. Classically, HCM is characterized by concentric myocardial hypertrophy with cardiomyocyte disarray. Outflow tract obstruction resulting from segmental septal hypertrophy or systolic anterior motion of the mitral valve often augments the disease. The majority of the genetic mutations reported in patients with familial HCM affect components of ...

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“…Mechanical Measurements in Skinned Rat Ventricular Myocytes-Rat ventricular myocytes were mechanically isolated and mounted in the experimental set-up as described previously (20). Isometric force production and the rate constant of force redevelopment (k tr ) were assessed in single, skinned myocytes, as described previously (20), before and after PKC␦ treatment alone (as described above) or in combination with Src kinase.…”

Section: Methodsmentioning

confidence: 99%

Tyrosine Phosphorylation Modifies Protein Kinase C δ-dependent Phosphorylation of Cardiac Troponin I

Sumandea

Rybin

Hinken

et al. 2008

Journal of Biological Chemistry

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PKC␦ leads to depressed maximum tension and cross-bridge kinetics, attributable to a dominant effect of cTnI-Thr144 phosphorylation. Our data implicate PKC␦-Tyr 311 /Thr 505 phosphorylation as dynamically regulated modifications that alter PKC␦ enzymology and allow for stimulus-specific control of cardiac mechanics during growth factor stimulation and oxidative stress. Protein kinase C␦ (PKC␦)2 is a ubiquitous serine/threonine kinase implicated in a wide range of cellular responses (1, 2). PKC␦ is conventionally viewed as a lipid-dependent enzyme that is anchored to membranes in close proximity to target substrates through interactions with lipid cofactors. However, there is recent evidence that PKC␦ also is dynamically regulated through activation loop (Thr 505 ) phosphorylation (3, 4). For other PKC isoforms, activation loop phosphorylation is a stable "priming" phosphorylation completed during de novo enzyme synthesis (5). In the case of cPKCs, activation loop phosphorylations are mediated by phosphoinositide-dependent kinase-1 and are essential to generate a catalytically competent enzyme. Although newly synthesized PKC␦ also undergoes maturational phosphoinositide-dependent kinase-1-dependent Thr 505 phosphorylation, PKC␦ differs from other PKC isoforms in that 1) PKC␦ is a catalytically active enzyme even without Thr 505 phosphorylation and 2) PKC␦-Thr 505 phosphorylation is dynamically regulated through an autocatalytic mechanism (4). Although there are hints that Thr 505 phosphorylation might contribute to the control of PKC␦ enzymology, a PKC␦-Thr 505 autophosphorylation mechanism that regulates the actions of PKC␦ toward a physiologically relevant substrate in a differentiated cell has never been reported.PKC␦ also is regulated through tyrosine phosphorylation. However, the consequences of PKC␦ tyrosine phosphorylation remain disputed, because PKC␦ tyrosine phosphorylation is variably linked to increased, decreased, or unchanged PKC␦ activity (1). Inconsistencies in the literature have been attributed to the presence of multiple tyrosine residues throughout the structure of PKC␦ (including

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Inorganic phosphate speeds loaded shortening in rat skinned cardiac myocytes

Cited by 34 publications

References 40 publications

Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities

Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities

Elevated Ca²⁺transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Tyrosine Phosphorylation Modifies Protein Kinase C δ-dependent Phosphorylation of Cardiac Troponin I

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Inorganic phosphate speeds loaded shortening in rat skinned cardiac myocytes

Cited by 34 publications

References 40 publications

Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities

Modulation of the rate of cardiac muscle contraction by troponin C constructs with various calcium binding affinities

Elevated Ca2+transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Tyrosine Phosphorylation Modifies Protein Kinase C δ-dependent Phosphorylation of Cardiac Troponin I

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Elevated Ca²⁺transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines