Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Poster Abstracts

2-DEOXY-ATP IMPROVES SYSTOLIC VENTRICULAR FUNCTION IN A MULTISCALE COMPUTATIONAL MODEL OF HEART FAILURE Abigail E Teitgen 1 ; Marcus Hock 1 ; Kimberly J McCabe 2 ; Matthew C Childers 3 ; Gary Huber 4 ; Daniel Beard 5 ; Michael Regnier 3 ; Andrew McCulloch 1 ; 1 University of California, San Diego, Bioengineering, San Diego, CA, USA 2 Simula Research Laboratory, Computational Physiology, Oslo, Norway 3 University of Washington, Bioengineering, Seattle, WA, USA 4 University of California, San Diego, Chemistry and Biochemistry, San Diego, CA, USA 5 University of Michigan, Molecular and Integrative Physiology, Ann Arbor, MI, USA 2-deoxy-ATP (dATP), a candidate therapeutic for heart failure, improves cardiac contractility and lusitropy by acting on myosin to increase the rate of crossbridge binding and cycling, and by increasing the rate of calcium transient decay. However, the molecular mechanisms behind these effects and how observed therapeutic responses to dATP are achieved – even when it is only a small fraction of the total ATP pool – remain poorly understood, especially in models of heart failure, in which energy metabolism is impaired. We developed a novel multiscale computational modeling framework to address these questions. We conducted molecular dynamics (MD) and Brownian dynamics (BD) simulations to assess (d)ADP.Pi-myosin/actin association rates. We then utilized these association rates to constrain a sarcomere mechanics model, and combined this with experimental calcium transient data to simulate the effects of dATP at the myocyte level. We then utilized a model of rat biventricular mechanics, energetics, and circulation to predict the effects of elevated dATP at the tissue and ventricular scales. MD and BD simulations showed that dATP increases actomyosin association rate via stabilization of pre-powerstroke myosin. Model predictions indicated that dATP destabilizes the super-relaxed state of myosin, leading to large changes in force with small fractions of dATP. The integrative effects of dATP on improved calcium handling and increased crossbridge binding and cycling augmented myocyte contractility and lusitropy, and could fully explain increases in myocyte shortening and relaxation observed experimentally. In a failing heart model, we predicted improvements in left ventricular function with no additional impairment of metabolic state with only 1% dATP. This was due at least in part to improved energy efficiency with elevated dATP. This novel multiscale analysis has elucidated how molecular mechanisms of dATP lead to improved cardiovascular function in heart failure.

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