Abstract
Dilated cardiomyopathy (DCM) is a life-threatening form of heart disease that is typically characterized by progressive thinning of the ventricular walls, chamber dilation, and systolic dysfunction. Multiple mutations in the gene encoding filamin C (FLNC), an actin-binding cytoskeletal protein in cardiomyocytes, have been found in patients with DCM. However, the mechanisms that lead to contractile impairment and DCM in patients with FLNC variants are poorly understood. To determine how FLNC regulates systolic force transmission and DCM remodeling, we used an inducible, cardiac-specific FLNC-knockout (icKO) model to produce a rapid onset of DCM in adult mice. Loss of FLNC reduced systolic force development in single cardiomyocytes and isolated papillary muscles but did not affect twitch kinetics or calcium transients. Electron and immunofluorescence microscopy showed significant defects in Z-disk alignment in icKO mice and altered myofilament lattice geometry. Moreover, a loss of FLNC induces a softening myocyte cortex and structural adaptations at the subcellular level that contribute to disrupted longitudinal force production during contraction. Spatially explicit computational models showed that these structural defects could be explained by a loss of inter-myofibril elastic coupling at the Z-disk. Our work identifies FLNC as a key regulator of the multiscale ultrastructure of cardiomyocytes and therefore plays an important role in maintaining systolic mechanotransmission pathways, the dysfunction of which may be key in driving progressive DCM.
Highlights
Dilated cardiomyopathy (DCM) is a common and life-threatening form of heart disease that affects 1 in ~250 individuals [1]
To determine the effects of filamin C (FLNC) deletion on cell and tissue-level systolic tension development, we measured the twitch mechanics and kinetics of electrically stimulated intact right-ventricular papillary muscles and single ventricular cardiomyocytes isolated from icKO and control hearts
The goal of this study was to elucidate the role of filamin C (FLNC) in regulating cardiac systolic contractile function and DCM [17] by measuring the structural and mechanical alterations in mouse cardiac muscle lacking FLNC and using multiscale models to investigate the mechanisms of altered force transmission and Z-disk coupling
Summary
Dilated cardiomyopathy (DCM) is a common and life-threatening form of heart disease that affects 1 in ~250 individuals [1]. In non-ischemic DCM, patients often carry loss-of-function mutations in genes encoding sarcomeric or cytoskeletal proteins, many of which mediate mechanotransmission, mechanosensing, and/or mechanotransduction in cardiomyocytes. Filamin C (FLNC) is a striated muscle-specific isoform of the actin-crosslinking filamin family and associates with multiple proteins in the Z-disk and costamere, including integrins, desmin, and α-actinin [7,8]. Hundreds of unique FLNC variants have been linked to cardiomyopathies [10], including many in arrhythmogenic cardiomyopathy [11,12] and multiple FLNC-truncating mutations in patients with DCM [10,13,14,15]. The role of FLNC in regulating cardiac mechanics and structure and the mechanisms by which the loss of full-length FLNC leads to a DCM phenotype are poorly understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
