Multiscale modeling shows how 2'-deoxy-ATP rescues ventricular function in heart failure

• 成果类型: Article
• 署名作者: Teitgen, Abigail E.; Hock, Marcus T.; Mccabe, Kimberly J.; Childers, Matthew C.; Huber, Gary A.; Marzban, Bahador; Beard, Daniel A.; McCammon, J. Andrew; Regnier, Michael; McCulloch, Andrew D.
• 署名单位: University of California System; University of California San Diego; University of Washington; University of Washington Seattle; University of California System; University of California San Diego; University of Michigan System; University of Michigan; University of California System; University of California San Diego
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14889
• DOI: 10.1073/pnas.2322077121
• 发表日期: 2024-08-27
• 关键词: cross-bridge; software package; force generation; atp hydrolysis; myosin; actin; activation; overexpression; contractility; mechanics

摘要

2'-deoxy-ATP (dATP) improves cardiac function by increasing the rate of crossbridge cycling and Ca2+ transient decay. However, the mechanisms of these effects and how therapeutic responses to dATP are achieved when dATP is only a small fraction of the total ATP pool remain poorly understood. Here, we used a multiscale computational modeling approach to analyze the mechanisms by which dATP improves ventricular function. We integrated atomistic simulations of prepowerstroke myosin mechanics, cell-scale analysis of myocyte Ca2+ dynamics and contraction, organ-scale modeling of biventricular mechanoenergetics, and systems level modeling of circulatory dynamics. Molecular and Brownian dynamics simulations showed that dATP increases increases the pool of myosin heads available for crossbridge cycling, increasing steadystate force development at low dATP fractions by 1.3 fold due to mechanosensing and nearest-neighbor cooperativity. This was found to be the dominant mechanism by which small amounts of dATP can improve contractile function at myofilament ventricular contractility, especially in a failing heart model in which dATP increased work represents a complete multiscale model analysis of a small molecule myosin with reduced ejection fraction.