Biophysical Society Thematic Meeting | Canterbury 2023

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

Thursday Speaker Abstracts

HARNESSING MULTISCALE MODELS TO UNDERSTAND DILATED CARDIOMYOPATHY THIN FILAMENT MUTATIONS Michael J. Greenberg ; 1 Washington University School of Medicine, Biochemistry and Molecular Biophysics, Saint Louis, MO, USA transplantation in both adult and pediatric patients. Excellent clinical studies have shown that point mutations in sarcomeric proteins including troponin T are prominent causes of dilated cardiomyopathy; however, genetic information is generally not considered when treating patients, in part, due to challenges connecting genotype and phenotype. Fundamentally, point mutations in proteins affect their structure, function, and/or abundance, but we do not have a good understanding of how molecular dysfunction is related to changes in cellular and tissue function. To begin to address this gap in our knowledge, we have applied multiscale tools to study point mutations in troponin T associated with dilated cardiomyopathy at the molecular, cellular, and tissue levels. We show that while different mutations in troponin T reduce cellular contractility, they do so with different molecular mechanisms. Moreover, we demonstrate how knowledge of molecular mechanism can be harnessed to identify compounds that improve tissue scale contractility for specific mutations. Taken together, our studies represent an important step in connecting genotype and phenotype across scales.

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