Biophysical Society Thematic Meeting | Canterbury 2023

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

Monday Speaker Abstracts

INTEGRATING MULTISCALE COMPUTATIONAL MODELS AND EXPERIMENTAL BIOMECHANICS TO INVESTIGATE THE CONTRACTILITY FILAMIN C DEFICIENT HEARTS Joseph D Powers 1,2 ; 1 University of Washington, Laboratory Medicine and Pathology, Seattle, WA, USA 2 University of Washington, Mechanical Engineering, Seattle, WA, USA Dilated cardiomyopathy (DCM) is a common and deadly form of heart disease that is typically characterized by progressive thinning of ventricular walls, chamber dilation, and systolic dysfunction. DCM is often associated with mutations in genes encoding sarcomere or cytoskeleton proteins that confer contractile dysfunction and adverse cellular remodeling via poorly understood mechanisms. One such protein is Filamin C (FLNC), which interacts with multiple proteins in the Z-disc and the costamere, suggesting that it is important for maintaining those structures and contributing to mechanical force transmission in the heart. Moreover, many mutations in the gene that encodes FLNC are associated with multiple forms of human cardiomyopathies, with many unique FLNC mutations found in patients with DCM. However, the mechanisms that lead to DCM in patients with FLNC variants are not known. The objective of this study was to elucidate mechanisms by which FLNC regulate systolic force transmission in the heart and how a loss of functional FLNC drives progressive DCM. To do so, we used a genetically engineered mouse model that enables inducible homozygous knockout of FLNC (FLNC-KO) in adult mice, which triggers a rapid DCM phenotype. Experimental biomechanics using single cardiomyocytes and papillary muscles isolated from FLNC-KO and control adult mouse hearts revealed a loss of contractility, but no effects on calcium signaling in FLNC-KO hearts compared to controls. Quantitative electron microscopy and immunofluorescent microscopy techniques were used to inform spatially explicit computational models of sarcomere/cell mechanics, which, together, revealed that a loss of FLNC induces adverse structural adaptations at the myofibril level that contribute to disrupted longitudinal force production during contraction. This work provides new insights into the pathological mechanisms by which dysfunctional FLNC promotes systolic abnormalities, subcellular remodeling, and the development of DCM.

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