# The role of cytoskeletal mechanotransduction and its regulation by Filamin C in pathological cardiac hypertrophy

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $26,839

## Abstract

Project Summary
Heart disease continues to be a global medical challenge and a major cause of mortality. Many forms of heart
disease are accompanied by hypertrophy and remodeling of the myocardium that increases the risk of sudden
cardiac death, making ventricular hypertrophy a leading predictor of contractile dysfunction and progressive heart
failure. Inherited cardiomyopathies represent a significant subset of hypertrophic heart disease, the two primary
forms being hypertrophic and dilated cardiomyopathy (HCM & DCM, respectively). HCM is characterized by a
concentric hypertrophy (thickening) of cardiomyocytes (CMs) and ventricular walls leading to diastolic
dysfunction, while DCM is characterized by eccentric CM hypertrophy (lengthening) and chamber dilation with
systolic dysfunction. Concentric HCM remodeling is often associated with sarcomeric mutations that confer a
gain of mechanical function, whereas dilated DCM remodeling is more typically associated with loss-of-function
sarcomeric mutations or mutations in genes encoding cytoskeletal proteins that may mediate
mechanotransmission or mechanotransduction in CMs. Our overall hypothesis is that differential hypertrophic
responses are regulated by the anisotropy of mechanical force transmission and external loading relative to the
myofibrillar axis such that mechanical alterations redistribute the axial versus radial components of CM stress
and strain (i.e., change the anisotropy of CM mechanics) are converted into signals that differentiate anisotropic
CM growth via distinct mechanosensors and mechanotransducers. Molecular complexes in the membrane and
cortical cytoskeleton of CMs are thought to serve as peripheral mechanosensors or transducers that likely
mediate differential hypertrophic responses. One such structure is the costamere, which links the sarcomere to
the cell membrane and contains vinculin and filamin C (FLNC). A loss of vinculin in mouse hearts was found to
cause DCM which was preceded by a reduction of cortical membrane stiffness that led to an increase in radial
systolic strain but not axial systolic strain in CMs. It is unknown if a loss of FLNC in the heart also dysregulates
cortical stiffness and anisotropy of systolic strain in CMs, but it has been shown that a loss of filamin in fibroblasts
reduces the anisotropy of intracellular force distributions in response to applied external mechanical loading. My
goal in this project is to employ a new mouse model with cardiac-specific and inducible FLNC deletion
and integrate nanoscale measurements of cytoskeletal mechanics, costameric loading distributions,
and mechanosensitive gene expression to test the hypothesis that FLNC regulates the relationship
between cortical cytoarchitecture, the anisotropy of intra-myocyte strain, and the transduction
mechanical stimuli into differential growth that underpins DCM. Using FLNC-null CMs, I will elucidate the
dependence of the anisotropy of forces in the cortical cytoskeleton on hypert...

## Key facts

- **NIH application ID:** 10249965
- **Project number:** 5F32HL152573-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JOSEPH D. POWERS
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $26,839
- **Award type:** 5
- **Project period:** 2020-05-07 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249965

## Citation

> US National Institutes of Health, RePORTER application 10249965, The role of cytoskeletal mechanotransduction and its regulation by Filamin C in pathological cardiac hypertrophy (5F32HL152573-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10249965. Licensed CC0.

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