Biophysical Society Thematic Meeting | Canterbury 2023

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

Monday Speaker Abstracts

FIBROBLAST-MEDIATED REGULATION OF CARDIAC STRUCTURE & STIFFNESS. Ross C Bretherton 1 ; Isabella M Reichardt 1 ; Kristin Zabrecky 2 ; Logan Bailey 2 ; Darrian Bugg 2 ; Timothy McMillen 3 ; Wolfgang Linke 5 ; Kristina Kooiker 4 ; Amy Martinson 2 ; Franziska Koser 5 ; Michael Regnier 1 ; Elizabeth Plaster 2 ; Jagadambika Gunaje 2 ; Galina Flint 1 ; Farid Moussavi Harami 2,4 ; Jennifer Davis 1,2 ; 1 University of Washington, Bioengineering, Seattle, WA, USA 2 University of Washington, Laboratory Medicine and Pathology, Seattle, WA, USA Inherited mutations in sarcomeric genes that decrease cardiomyocyte tension generation are drivers of dilated cardiomyopathy (DCM). Developing precision therapeutics for and mechanistic studies of inherited DCM have been solely focused on cardiomyocytes with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of DCM severity, cardiac fibrosis. Because the ability to reverse or even slow fibrosis remains a major limitation of both standard of care and first in class therapeutics for DCM, this study examined whether cardiac fibroblast-mediated regulation of the heart’s mechanical properties is essential for DCM outcomes. Using a mouse model of inherited DCM we found that prior to the onset of fibrosis and dilated myocardial remodeling both the myocardium and extracellular matrix (ECM) stiffen from switches in titin isoform expression, enhanced collagen fiber alignment, and expansion of the cardiac fibroblast population, which we blocked by genetically suppressing p38 specifically in cardiac fibroblasts. This fibroblast-targeted intervention unexpectedly improved the primary myocyte deficit in force generation and reversed ECM and dilated myocardial remodeling. Together these findings challenge the long-standing paradigm that ECM remodeling is a secondary complication to inherited defects in cardiomyocyte contractile function and instead demonstrate cardiac fibroblasts are essential contributors to the DCM phenotype, thus suggesting DCM-specific therapeutics will require fibroblast-specific strategies. 3 University of Washington, Anesthesiology, Seattle, WA, USA 4 University of Washington, Medicine/Cardiology, Seattle, WA, USA 5 University of Münster, Physiology, Münster, Germany

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