Hypertrophic cardiomyopathy (HCM) is one of the most common heritable cardiovascular diseases and variants of (cardiac troponin T) are linked to increased risk of sudden cardiac arrest despite causing limited hypertrophy. In this study, a variant, R278C, was generated in both human cardiac recombinant/reconstituted thin filaments (hcRTF) and human- induced pluripotent stem cells (hiPSCs) to investigate the mechanisms by which the R278C variant affects cardiomyocytes at the proteomic and functional levels. The results of proteomics analysis showed a significant upregulation of markers of cardiac hypertrophy and remodeling in R278C vs.
View Article and Find Full Text PDFAtten Percept Psychophys
July 2023
Working memory (WM) is the ability to maintain and manipulate information no longer accessible in the environment. The brain maintains WM representations over delay periods in noisy population-level activation patterns, resulting in variability in WM representations across items and trials. It is established that participants can introspect aspects of the quality of WM representations, and that they can accurately compare which of several WM representations of stimulus features like orientation or color is better on each trial.
View Article and Find Full Text PDFCardiac troponin C (cTnC) is the critical Ca -sensing component of the troponin complex. Binding of Ca to cTnC triggers a cascade of conformational changes within the myofilament that culminate in force production. Hypertrophic cardiomyopathy (HCM)-associated TNNC1 variants generally induce a greater degree and duration of Ca binding, which may underly the hypertrophic phenotype.
View Article and Find Full Text PDFHypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease and often results in cardiac remodeling and an increased incidence of sudden cardiac arrest (SCA) and death, especially in youth and young adults. Among thousands of different variants found in HCM patients, variants of (cardiac troponin T-TNNT2) are linked to increased risk of ventricular arrhythmogenesis and sudden death despite causing little to no cardiac hypertrophy. Therefore, studying the effect of variants on cardiac propensity for arrhythmogenesis can pave the way for characterizing HCM in susceptible patients before sudden cardiac arrest occurs.
View Article and Find Full Text PDFCardiac muscle thin filaments are composed of actin, tropomyosin, and troponin that change conformation in response to Ca binding, triggering muscle contraction. Human cardiac troponin C (cTnC) is the Ca-sensing component of the thin filament. It contains structural sites (III/IV) that bind both Ca and Mg and a regulatory site (II) that has been thought to bind only Ca.
View Article and Find Full Text PDFThe zebrafish has proven to be an excellent organism for manipulation of its genome from a long history of transcript down-regulation using morpholino oligimers to more recent genome editing tools such as CRISPR-Cas9. Early forward and reverse genetic screens significantly benefited from the transparency of zebrafish embryos, allowing cardiac development as a function of genetics to be directly observed. However, gradual loss of transparency with subsequent maturation limited many of these approaches to the first several days post-fertilization.
View Article and Find Full Text PDFSudden unexpected death of an infant (SUDI) is a devastating occurrence for families. To investigate the genetic pathogenesis of SUDI, we sequenced >70 genes from 191 autopsy-negative SUDI victims. Ten infants sharing a previously unknown variant in troponin I (TnI) were identified.
View Article and Find Full Text PDFThe zebrafish (Danio rerio) heart is a viable model of mammalian cardiovascular function due to similarities in heart rate, ultrastructure, and action potential morphology. Zebrafish are able to tolerate a wide range of naturally occurring temperatures through altering chronotropic and inotropic properties of the heart. Optical mapping of cannulated zebrafish hearts can be used to assess the effect of temperature on excitation-contraction (EC) coupling and to explore the mechanisms underlying voltage (V) and calcium (Ca) transients.
View Article and Find Full Text PDFRev Physiol Biochem Pharmacol
June 2017
Zebrafish (Danio rerio) are widely used as vertebrate model in developmental genetics and functional genomics as well as in cardiac structure-function studies. The zebrafish heart has been increasingly used as a model of human cardiac function, in part, due to the similarities in heart rate and action potential duration and morphology with respect to humans. The teleostian zebrafish is in many ways a compelling model of human cardiac function due to the clarity afforded by its ease of genetic manipulation, the wealth of developmental biological information, and inherent suitability to a variety of experimental techniques.
View Article and Find Full Text PDFZebrafish, as a model for teleost fish, have two paralogous troponin C (TnC) genes that are expressed in the heart differentially in response to temperature acclimation. Upon Ca(2+) binding, TnC changes conformation and exposes a hydrophobic patch that interacts with troponin I and initiates cardiac muscle contraction. Teleost-specific TnC paralogs have not yet been functionally characterized.
View Article and Find Full Text PDFThe Ca(2+) binding properties of the FHC-associated cardiac troponin C (cTnC) mutation L29Q were examined in isolated cTnC, troponin complexes, reconstituted thin filament preparations, and skinned cardiomyocytes. While higher Ca(2+) binding affinity was apparent for the L29Q mutant in isolated cTnC, this phenomenon was not observed in the cTn complex. At the level of the thin filament in the presence of phosphomimetic TnI, L29Q cTnC further reduced the Ca(2+) affinity by 27% in the steady-state measurement and increased the Ca(2+) dissociation rate by 20% in the kinetic studies.
View Article and Find Full Text PDFThe amino-terminal regulatory domain of cardiac troponin C (cNTnC) plays an important role as the calcium sensor for the troponin complex. Calcium binding to cNTnC results in conformational changes that trigger a cascade of events that lead to cardiac muscle contraction. The cardiac N-terminal domain of TnC consists of two EF-hand calcium binding motifs, one of which is dysfunctional in binding calcium.
View Article and Find Full Text PDF