Cardiac System during the Aging Process

Aging and Disease, Год журнала: 2023, Номер unknown, С. 0 - 0

Опубликована: Янв. 1, 2023

The aging process is accompanied by a continuous decline of the cardiac system, disrupting homeostatic regulation cells, organs, and systems. Aging increases prevalence cardiovascular diseases, thus heart failure mortality. Understanding pivotal importance once it allows us to design strategies prevent age-related events increasing quality live in elderly. In this review we provide an overview focus on following topics: structural functional modifications; cellular mechanisms dysfunction aging; genetics epigenetics development diseases; response exercise.

Язык: Английский

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Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders

JAMA Psychiatry, Год журнала: 2024, Номер 81(9), С. 870 - 870

Опубликована: Май 22, 2024

Importance The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells dorsolateral prefrontal cortex that especially vulnerable cognitive disorders. Objective To examine molecular mechanisms expressed primate cortices. Design, Setting, Participants design included transcriptomic analyses from human macaque cortex, connectivity, protein expression, physiology, behavior macaques. research was performed academic laboratories at Yale, Harvard, Princeton, University Pittsburgh. As only exists primates, work evaluated humans Main Outcomes Measures Outcome measures signatures cells, expression interactions using light electron microscopy, changes neuronal firing during spatial working memory, memory performance following pharmacological treatments. Results Layer coexpress a constellation calcium-related proteins, delineated by CALB1 (calbindin), high levels (Cav1.2), GRIN2B (NMDA receptor GluN2B), KCNN3 (SK3 potassium channel), concentrated dendritic spines near calcium-storing smooth endoplasmic reticulum. L-type influenced needed for where either blockade or increased drive β1-adrenoceptors, reduced mean (SD) 37.3% (5.5%) 40% (6.3%), respectively, latter via SK opening. An blocker β1-adrenoceptor antagonist protected stress. Conclusions Relevance differentially express calbindin proteins including Cav1.2 ( ), GluN2B-NMDA receptors SK3 which influence memory-related firing. finding inadequate excessive activation explains loss- gain-of-function were selective highlights importance regulatory neurons signaling, consistent Alzheimer tau pathology emerging when lost age and/or inflammation.

Язык: Английский

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Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 15, 2024

Язык: Английский

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Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

The Journal of General Physiology, Год журнала: 2022, Номер 154(9)

Опубликована: Апрель 28, 2022

Each heartbeat begins with the generation of an action potential in pacemaking cells sinoatrial node. This signal triggers contraction cardiac muscle through a process termed excitation-contraction (EC) coupling. EC coupling is initiated dyadic structures myocytes, where ryanodine receptors junctional sarcoplasmic reticulum come into close apposition clusters CaV1.2 channels invaginations sarcolemma. Cooperative activation within these causes local increase intracellular Ca2+ that activates juxtaposed receptors. A salient feature healthy function reliable and precise beat-to-beat amplitude transients during In this review, we discuss recent discoveries suggesting exquisite reproducibility system emerges, paradoxically, from high variability at subcellular, cellular, network levels. attributable to stochastic fluctuations ion channel trafficking, clustering, gating, as well structure, which variance Although effects large, organization are sometimes negligible macroscopic level owing spatial-temporal summation across tissue, work suggests "noisiness" events may either enhance or counterintuitively reduce context-dependent manner. Indeed, noisy represent distinct regulatory features tuning contractility. Collectively, observations support importance incorporating experimentally determined values all models. The paradoxical outcome signaling levels caused by multiple processes time space. underlying stochasticity, manifests reliable, consistent coupling, also allows for rapid changes rhythmicity contractility health disease.

Язык: Английский

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Endoplasmic Reticulum–Plasma Membrane Junctions as Sites of Depolarization-Induced Ca²⁺Signaling in Excitable Cells

Annual Review of Physiology, Год журнала: 2022, Номер 85(1), С. 217 - 243

Опубликована: Окт. 6, 2022

Membrane contact sites between endoplasmic reticulum (ER) and plasma membrane (PM), or ER-PM junctions, are found in all eukaryotic cells. In excitable cells they play unique roles organizing diverse forms of Ca

Язык: Английский

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Homo sapiens—A Species Not Designed for Space Flight: Health Risks in Low Earth Orbit and Beyond, Including Potential Risks When Traveling beyond the Geomagnetic Field of Earth

Life, Год журнала: 2023, Номер 13(3), С. 757 - 757

Опубликована: Март 10, 2023

Homo sapiens and their predecessors evolved in the context of boundary conditions Earth, including a 1 g gravity geomagnetic field (GMF). These variables, plus others, led to complex organisms that under defined set define how humans will respond space flight, circumstance could not have been anticipated by evolution. Over past ~60 years, flight living low Earth orbit (LEO) revealed astronauts are impacted varying degrees such new environments. In addition, it has noted quite heterogeneous response patterns, indicating variation is either silent if one remained on or heterogeneity unknowingly contributes disease development during aging insults. With planned mission deep space, now be exposed further risks from radiation when traveling beyond influence GMF, as well other potential associated with actual loss GMF astronauts, microbiomes, growing food sources. Experimental studies model systems hypogravity can variety biological physiological systems, thus may unanticipated consequences astronauts’ those electrical nature (i.e., cardiovascular system central neural systems). As shown responses LEO, they require personalized countermeasures, while others good candidates for deep-space missions effective countermeasures cannot developed long-duration missions. This review discuss several affected emerging variables astronaut health functioning.

Язык: Английский

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BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Апрель 25, 2024

Abstract Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels the hearts 24-month-old mice rejuvenates cardiac function substantially reverses phenotype. Our data indicate age-associated overexpression BIN1 occurs alongside dysregulated endosomal recycling disrupted trafficking Ca V 1.2 type 2 ryanodine receptors. These deficiencies affect channel at rest their upregulation during acute stress. In vivo echocardiography reveals reduced systolic old knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores nanoscale distribution clustering plasticity receptors recovers 2+ transient amplitudes toward levels. Enhanced correlates with increased phosphorylation myofilament protein myosin binding protein-C. results reveal as novel therapeutic strategy rejuvenate myocardium.

Язык: Английский

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Spatiotemporal Control of Vascular Ca _V 1.2 by α1 _C S1928 Phosphorylation

Circulation Research, Год журнала: 2022, Номер 131(12), С. 1018 - 1033

Опубликована: Ноя. 8, 2022

L-type Ca

Язык: Английский

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Amphiphysin-2 (BIN1) functions and defects in cardiac and skeletal muscle

Trends in Molecular Medicine, Год журнала: 2024, Номер 30(6), С. 579 - 591

Опубликована: Март 20, 2024

Язык: Английский

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Plasma membrane curvature regulates the formation of contacts with the endoplasmic reticulum

Nature Cell Biology, Год журнала: 2024, Номер 26(11), С. 1878 - 1891

Опубликована: Сен. 17, 2024

Contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) play a crucial role in governing calcium regulation lipid homeostasis. Despite their significance, factors regulating spatial distribution on PM remain elusive. Inspired by observations cardiomyocytes, where ER-PM contact concentrate tubular invaginations known as transverse tubules, we hypothesize that curvature plays formation. Through precise control of invaginations, show curvatures locally induce formation contacts cardiomyocytes. Intriguingly, junctophilin family tethering proteins, specifically expressed excitable cells, is key player this process, whereas ubiquitously extended synaptotagmin-2 does not preference for curvature. At mechanistic level, find low-complexity region (LCR) occupation recognition nexus (MORN) motifs junctophilins can bind independently to PM, but both LCR MORN are required targeting curvatures. By examining interactome, identify curvature-sensing proteins-Eps15 homology domain-containing proteins-that interact with MORN_LCR facilitate preferential curved PM. These findings highlight pivotal cardiomyocytes unveil mechanism through modulation.

Язык: Английский

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