Why the study?
The mechanisms leading to contractile impairment and dilated cardiomyopathy in patients with FLNC variants are poorly understood.
Does loss of FLNC impair systolic force transmission and induce dilated cardiomyopathy remodeling in adult mice?
Does loss of FLNC impair systolic force transmission and induce dilated cardiomyopathy remodeling in adult mice?
FLNC is a key regulator of cardiomyocyte multiscale ultrastructure, and its loss disrupts inter-myofibril elastic coupling at the Z-disk, leading to impaired systolic mechanotransmission and progressive dilated cardiomyopathy.
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.
No takes yet. Share an insight, caveat, or question.
Powers et al. (2022) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: