Age-dependent biochemical and contractile properties in atrium of transgenic mice overexpressing junctin

2004 ◽  
Vol 287 (5) ◽  
pp. H2216-H2225 ◽  
Author(s):  
Uwe Kirchhefer ◽  
Hideo A. Baba ◽  
Gabriela Hanske ◽  
Larry R. Jones ◽  
Paulus Kirchhof ◽  
...  
Keyword(s):  
Heart Rate ◽  
Transgenic Mice ◽  
Ryanodine Receptor ◽  
Transmembrane Protein ◽  
Force Of Contraction ◽  
Stress Tests ◽  
Age Dependent ◽  
Beating Rate ◽  
Right Atria ◽  
Junctional Sarcoplasmic Reticulum

Junctin is a transmembrane protein of the cardiac junctional sarcoplasmic reticulum (SR) that binds to the ryanodine receptor, calsequestrin, and triadin 1. This quaternary protein complex is thought to facilitate SR Ca2+ release. To improve our understanding of the contribution of junctin to the regulation of SR function, we examined the age-dependent effects of junctin overexpression in the atrium of 3-, 6-, and 18-wk-old transgenic mice. The ratio of atrial weight and body weight was unchanged between junctin-overexpressing (JCN) and wild-type (WT) mice at all ages investigated ( n = 6–8). The protein expression of triadin 1 was decreased starting in 3-wk-old JCN atria (by 69%), whereas the expression of the ryanodine receptor was diminished in 6- (by 48%) and 18-wk-old (by 57%) JCN atria compared with age-matched WT atria. Force of contraction was decreased by 35% in 18-wk-old JCN compared with age-matched WT left atrial muscle strips, which was accompanied by a prolonged time of relaxation (48.1 ± 0.9 vs. 44.2 ± 0.8 ms, respectively, n = 6–8, P < 0.05). The spontaneous beating rate of isolated right atria was higher in 18-wk-old JCN mice compared with age-matched WT mice (389 ± 10 vs. 357 ± 6 beats/min, respectively, n = 6–8, P < 0.05). Heart rate was lower by 9% in telemetric ECG recordings in 18-wk-old JCN mice during stress tests. Three-week-old JCN atria exhibited a higher potentiation of force of contraction at rest pauses of 30 s (by 13%) and of 300 s (by 35%), suggesting increased SR Ca2+ content. This was consistent with the higher force of contraction in 3-wk-old JCN atria (by 29%) compared with age-matched WT atria (by 10%) under the administration of caffeine. We conclude that in 3-wk-old atria, junctin overexpression was associated with a reduced expression of triadin 1 resulting in a higher SR Ca2+ load without changes in contractility or heart rate. In 6-wk-old JCN atria, the compensatory downregulation of the ryanodine receptor may offset the effects of junctin overexpression. Finally, the progressive decrease in ryanodine receptor density may contribute to the decreased atrial contractility and lower heart rate during stress in 18-wk-old JCN mice.

Altered function in atrium of transgenic mice overexpressing triadin 1

2002 ◽  
Vol 283 (4) ◽  
pp. H1334-H1343 ◽  
Author(s):  
Uwe Kirchhefer ◽  
Hideo A. Baba ◽  
Yvonne M. Kobayashi ◽  
Larry R. Jones ◽  
Wilhelm Schmitz ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Protein Expression ◽  
Ryanodine Receptor ◽  
Time Dependent ◽  
Force Of Contraction ◽  
Sr Protein ◽  
Inhibitory Function ◽  
Slow Twitch Muscle ◽  
Old Mice

Triadin 1 is a protein in the cardiac junctional sarcoplasmic reticulum (SR) that interacts with the ryanodine receptor, junctin, and calsequestrin, proteins that are important for Ca2+ release. To better understand the role of triadin 1 in SR-Ca2+ release, we studied the time-dependent expression of SR proteins and contractility in atria of 3-, 6-, and 18-wk-old transgenic mice overexpressing canine cardiac triadin 1 under control of the α-myosin heavy chain (MHC) promoter. Three-week-old transgenic atria exhibited mild hypertrophy. Finally, atrial weight was increased by 110% in 18-wk-old transgenic mice. Triadin 1 overexpression was accompanied by time-dependent changes in the protein expression of the ryanodine receptor, junctin, and cardiac/slow-twitch muscle SR Ca2+-ATPase isoform. Force of contraction was already decreased in 3-wk-old transgenic atria. The application of caffeine led to a positive inotropic effect in transgenic atria of 3-wk-old mice. Rest pauses resulted in an increased potentiation of force of contraction after restimulation in 3- and 6-wk-old mice and a reduced potentiation of force of contraction in 18-wk-old transgenic mice. Hence, triadin 1 overexpression triggered time-dependent alterations in SR protein expression, Ca2+homeostasis, and contractility, indicating for the first time an inhibitory function of triadin 1 on SR-Ca2+ release in vivo.

scholarly journals Multiple regions of junctin drive interaction with calsequestrin-1 and localization at triads in skeletal muscle

2021 ◽  
Author(s):  
Daniela Rossi ◽  
Stefania Lorenzini ◽  
Enrico Pierantozzi ◽  
Filip Van Petegem ◽  
David Osamwonuyi Amadsun ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Ryanodine Receptor ◽  
Transmembrane Protein ◽  
Sr Proteins ◽  
Receptor Interaction ◽  
Striated Muscles ◽  
Charged Amino Acids ◽  
Multiple Regions ◽  
Junctional Sarcoplasmic Reticulum

Junctin is a transmembrane protein of striated muscles, localized at the junctional sarcoplasmic reticulum (j-SR). It is characterized by a luminal C-terminal tail, through which it functionally interacts with calsequestrin and the ryanodine receptor. Interaction with calsequestrin was ascribed to the presence of stretches of charged amino acids. However, the regions able to bind calsequestrin have not been defined in detail. We report here that, in non-muscle cells, junctin and calsequestrin assemble in long linear regions within the endoplasmic reticulum, mirroring the formation of calsequestrin polymers. In differentiating myotubes, the two proteins co-localize at triads, where they assemble with other j-SR proteins. By performing GST pull-down assays with distinct regions of the junctin tail, we identified two KEKE motifs able to bind calsequestrin. In addition, stretches of charged amino acids downstream these motifs were found to be also able to bind calsequestrin and the ryanodine receptor. Deletion of even one of these regions impaired the ability of junctin to localize at the j-SR, suggesting that interaction with other proteins at this site represents a key element in junctin targeting.

Effects of a specific bradycardic agent (AQ-A39) and verapamil on β-adrenergic responses in isolated guinea pig atria

1987 ◽  
Vol 65 (2) ◽  
pp. 146-151 ◽  
Author(s):  
Peter K. S. Siegl ◽  
George Morgan
Keyword(s):  
Heart Rate ◽  
Guinea Pig ◽  
Channel Blocker ◽  
Cardiac Contractility ◽  
Force Of Contraction ◽  
Bradycardic Agent ◽  
Inotropic Responses ◽  
Right Atria ◽  
Guinea Pig Atria ◽  
Elevated Heart Rate

AQ-A39 (5,6-dimethoxy-2-{3-[(α-(3,4-dimethoxy)phenylethyl)methylamino]propyl}-phthalimidine), a specific bradycardic agent, and verapamil, a calcium channel blocker, were studied for their ability to alter rate and force of contraction in the presence and absence of isoproterenol, a β-adrenergic stimulant, using isolated guinea pig atria. Both compounds (10−7–10−4 M) produced dose-related decreases in frequency of spontaneously beating right atria. Verapamil decreased, while AQ-A39 increased, the force of contraction of electrically stimulated (1.0 Hz) left atria. At equal negative chronotropic concentrations, AQ-A39 was more effective than verapamil in reducing the maximum isoproterenol-induced tachycardia. Verapamil, but not AQ-A39, antagonized positive inotropic responses to isoproterenol. Therefore, AQ-A39 differed from verapamil in that (i) AQ-A39 was a more selective bradycardic agent in both β-adrenergically stimulated and nonstimulated preparations and (ii) AQ-A39 was more effective in reducing isoproterenol-elevated heart rate compared with basal heart rate. This profile of activities suggests that AQ-A39 will be beneficial in cardiac pathologies where sympathetic nervous system activity is elevated and a lowering of heart rate without a reduction in cardiac contractility is desired.

Stroke-induced opposite and age-dependent changes of vessel-associated markers in co-morbid transgenic mice with Alzheimer-like alterations

2013 ◽  
Vol 250 ◽  
pp. 270-281 ◽  
Author(s):  
Cheryl A. Hawkes ◽  
Dominik Michalski ◽  
Rebecca Anders ◽  
Sabine Nissel ◽  
Jens Grosche ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Age Dependent

scholarly journals Age-dependent formation of TMEM106B amyloid filaments in human brain

2021 ◽  
Author(s):  
Manuel Schweighauser ◽  
Diana Arseni ◽  
Melissa Huang ◽  
Sofia Lövestam ◽  
Yang Shi ◽  
...  
Keyword(s):  
Human Brain ◽  
Transmembrane Protein ◽  
Amyloid Β ◽  
Dependent Manner ◽  
Type Ii ◽  
Western Blots ◽  
Normal Individuals ◽  
Age Dependent ◽  
Neurologically Normal ◽  
Filamentous Inclusions

Many age-dependent neurodegenerative diseases, like Alzheimer's and Parkinson's, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β (Aβ), α-synuclein and TDP-43 are the most common. Here, we used electron cryo-microscopy (cryo-EM) structure determination to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in the human brain. We solved cryo-EM structures of TMEM106B filaments from the brains of 22 individuals with neurodegenerative conditions, including sporadic and inherited tauopathies, Aβ-amyloidoses, synucleinopathies and TDP-43opathies, as well as from the brains of two neurologically normal individuals. We observed three different TMEM106B folds, with no clear relationship between folds and diseases. The presence of TMEM106B filaments correlated with that of a 29 kDa sarkosyl-insoluble fragment of the protein on Western blots. The presence of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.

scholarly journals IFITM3 protects the heart during influenza virus infection

2019 ◽  
Author(s):  
Adam D. Kenney ◽  
Temet M. McMichael ◽  
Alexander Imas ◽  
Nicholas M. Chesarino ◽  
Lizhi Zhang ◽  
...  
Keyword(s):  
Heart Rate ◽  
Influenza Virus ◽  
Virus Infection ◽  
Cardiac Dysfunction ◽  
Influenza A ◽  
Transmembrane Protein ◽  
Influenza Virus Infection ◽  
Small Animal ◽  
Heart Tissue ◽  
Underlying Mechanisms

AbstractInfluenza virus primarily targets the lungs, but dissemination and damage to heart tissue is also known to occur in severe infections. Despite this knowledge, influenza virus-induced cardiac pathogenesis and its underlying mechanisms have been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding interferon-induced transmembrane protein 3 (IFITM3), an antiviral restriction factor, are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to other aspects of pathogenesis, including cardiac dysfunction, is unknown. We now show that IFITM3 deficiency in a newly generated knockout (KO) mouse model exacerbates illness and mortality following influenza A virus infection. Enhanced pathogenesis correlated with increased replication of virus in the lungs, spleens, and hearts of KO mice relative to wildtype (WT) mice. IFITM3 KO mice exhibited normal cardiac function at baseline, but developed severely aberrant electrical activity upon infection, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals. In contrast, WT mice exhibited a mild decrease in heart rate without irregularity of RR intervals. Heightened cardiac virus titers and electrical dysfunction in KO animals was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Our findings reveal an essential role for IFITM3 in controlling influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model to study virus-induced cardiac dysfunction.

scholarly journals FETAL TYPE CLASSIFICATION BASED ON FETAL ELECTROCARDIOGRAPH IN NON-STRESS TESTS

2021 ◽  
pp. 2140052
Author(s):  
JIANLI LIU ◽  
YIMIN YANG ◽  
SONG ZHANG ◽  
XUWEN LI ◽  
LIN YANG ◽  
...  
Keyword(s):  
Heart Rate ◽  
Fetal Heart Rate ◽  
Fetal Heart ◽  
Classification Model ◽  
Support Vector ◽  
Stress Tests ◽  
Nonlinear Parameters ◽  
Design Algorithm ◽  
Long Time

Electronic fetal heart rate (FHR) monitoring is a technical means to evaluate the state of the fetus in the uterus by monitoring FHR. The main purpose is to detect intrauterine hypoxia and take corresponding medical measures timely. Because the fetus sleeps quietly for up to 1 hour sometimes, ultrasound Doppler is not easy to continuously detect for a long time. The electronic fetal monitor obtains the fetal heart rate, which not only improves the accuracy and comfort, but also the convenient implementation of long-term monitoring. It is beneficial to reduce perinatal fetal morbidity and mortality. This study used maternal–fetal Holter monitor which is based on the technology of fetal electrocardiograph (FECG) to collect the FHR, and then design algorithm to extract the baseline FHR, acceleration, variation, sleep-wake cycle and nonlinear parameters. There were significant differences in the 22 parameters between the normal and the suspicious group. Using the 22 characteristic parameters, the support vector machine was used to classify the normal and the suspected group of fetuses. 80% of the data was used to train a classification model. The remaining 20% of the data was used as a test set and its accuracy reached 93.75%.

scholarly journals Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca2+signaling

2014 ◽  
Vol 306 (10) ◽  
pp. H1385-H1397 ◽  
Author(s):  
Jie Liu ◽  
Syevda Sirenko ◽  
Magdalena Juhaszova ◽  
Steven J. Sollott ◽  
Shweta Shukla ◽  
...  
Keyword(s):  
Heart Rate ◽  
Cell Function ◽  
Ryanodine Receptors ◽  
Phosphodiesterase Inhibitor ◽  
Receptor Activation ◽  
Functional Changes ◽  
Adult Mice ◽  
Size Number ◽  
Pathway Activation ◽  
Beating Rate

A reduced sinoatrial node (SAN) functional reserve underlies the age-associated decline in heart rate acceleration in response to stress. SAN cell function involves an oscillatory coupled-clock system: the sarcoplasmic reticulum (SR), a Ca2+clock, and the electrogenic-sarcolemmal membrane clock. Ca2+-activated-calmodulin-adenylyl cyclase/CaMKII-cAMP/PKA-Ca2+signaling regulated by phosphodiesterase activity drives SAN cells automaticity. SR-generated local calcium releases (LCRs) activate Na+/Ca2+exchanger in the membrane clock, which initiates the action potential (AP). We hypothesize that SAN cell dysfunctions accumulate with age. We found a reduction in single SAN cell AP firing in aged (20–24 mo) vs. adult (3–4 mo) mice. The sensitivity of the SAN beating rate responses to both muscarinic and adrenergic receptor activation becomes decreased in advanced age. Additionally, age-associated coincident dysfunctions occur stemming from compromised clock functions, including a reduced SR Ca2+load and a reduced size, number, and duration of spontaneous LCRs. Moreover, the sensitivity of SAN beating rate to a cAMP stress induced by phosphodiesterase inhibitor is reduced, as are the LCR size, amplitude, and number in SAN cells from aged vs. adult mice. These functional changes coincide with decreased expression of crucial SR Ca2+-cycling proteins, including SR Ca2+-ATPase pump, ryanodine receptors, and Na+/Ca2+exchanger. Thus a deterioration in intrinsic Ca2+clock kinetics in aged SAN cells, due to deficits in intrinsic SR Ca2+cycling and its response to a cAMP-dependent pathway activation, is involved in the age-associated reduction in intrinsic resting AP firing rate, and in the reduction in the acceleration of heart rate during exercise.

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