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Cardiac‐specific Deletion of Filamin C Decouples Myocyte Contractility and Calcium Handling in Adult Mice
Author(s) -
Powers Joseph D.,
Liu Canzhao,
Fang Xi,
Omens Jeffrey H.,
Chen Ju,
McCulloch Andrew D.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04277
Subject(s) - sarcomere , myofilament , filamin , contractility , intercalated disc , myocyte , microbiology and biotechnology , medicine , chemistry , endocrinology , biology , cytoskeleton , cell , biochemistry , intracellular , gap junction
Costameres are sub‐membranous protein complexes in striated muscle that play roles in mechanical signal transduction and force transmission between the Z‐disc of the sarcomere and the extracellular matrix. In cardiac myocytes (CMs), the cytoskeletal protein Filamin C (FLNC) interacts with multiple proteins in the Z‐disc and the costamere, suggesting that it contributes to costamere‐based mechanotransduction in the heart. Moreover, mutations in the gene that encodes FLNC have been associated with multiple forms of human cardiomyopathies. To investigate the role of FLNC in cardiac mechanosignaling and pathological remodeling, we employed a recently developed murine model of inducible and cardiac‐specific FLNC knockout (FLNC‐icKO). Previous studies with this mouse model used echocardiographic measurements of adult FLNC‐icKO mice to reveal a severe dilated cardiomyopathy (DCM) phenotype by 2 weeks post‐induction, including significantly reduced ventricular fractional shortening. Correspondingly, we found that intact papillary muscles dissected from adult FLNC‐icKO hearts have significantly reduced twitch force compared to those dissected from wild‐type (WT) hearts. Interestingly, while the fractional shortening of isolated CMs from FLNC‐icKO hearts is also significantly reduced compared to WT CMs, the calcium transient (peak amplitude and duration) during a twitch is not different between groups. These results suggest that contractility and calcium handling in FLNC‐null hearts are decoupled. Potential mechanisms that may be responsible for this apparent decoupling are a disruption in force transmission between the sarcomere and the cell membrane, an increased myofilament lattice spacing, or altered calcium sensitivity of the myofilaments upon the deletion of FLNC in CMs. Support or Funding Information Funding: HL007444‐36 to JDP, HL144872 to JC, and HL137100 to ADM.