{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:43:48Z","timestamp":1789580628547,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["F32-HL152573"],"award-info":[{"award-number":["F32-HL152573"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["K99-HL159224"],"award-info":[{"award-number":["K99-HL159224"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["T32-HL007444"],"award-info":[{"award-number":["T32-HL007444"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL121754"],"award-info":[{"award-number":["R01 HL121754"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["20POST35180048"],"award-info":[{"award-number":["20POST35180048"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms23020871","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T03:14:03Z","timestamp":1642130043000},"page":"871","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Subcellular Remodeling in Filamin C Deficient Mouse Hearts Impairs Myocyte Tension Development during Progression of Dilated Cardiomyopathy"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7841-2337","authenticated-orcid":false,"given":"Joseph D.","family":"Powers","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie J.","family":"Kirkland","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9035-5723","authenticated-orcid":false,"given":"Canzhao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swithin S.","family":"Razu","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1642-5380","authenticated-orcid":false,"given":"Adam J.","family":"Engler","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"McCulloch","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Institute for Engineering in Medicine, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1161\/CIRCRESAHA.116.309396","article-title":"Dilated Cardiomyopathy: Genetic Determinants and Mechanisms","volume":"121","author":"McNally","year":"2017","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/cvr\/cvv023","article-title":"Targets for therapy in sarcomeric cardiomyopathies","volume":"105","author":"Tardiff","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1172\/JCI62862","article-title":"Genetic mutations and mechanisms in dilated cardiomyopathy","volume":"123","author":"McNally","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_4","unstructured":"Bang, M., Bogomolovas, J., and Chen, J. (2021). Understanding the Molecular Basis of Cardiomyopathy. Am. J. Physiol. Circ. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ppedcard.2011.02.003","article-title":"The costamere bridges sarcomeres to the sarcolemma in striated muscle","volume":"31","author":"Peter","year":"2011","journal-title":"Prog. Pediatr. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"H2291","DOI":"10.1152\/ajpheart.00749.2005","article-title":"Costameres, focal adhesions, and cardiomyocyte mechanotransduction","volume":"289","author":"Samarel","year":"2005","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0167-4889(01)00072-6","article-title":"Structural and functional aspects of filamins","volume":"1538","author":"Sonnenberg","year":"2001","journal-title":"Biochim. Biophys. Acta\u2014Mol. Cell Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Mao, Z., and Nakamura, F. (2020). Structure and Function of Filamin C in the Muscle Z-Disc. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082696"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-biophys-050511-102252","article-title":"Filamins in Mechanosensing and Signaling","volume":"41","author":"Razinia","year":"2012","journal-title":"Annu. Rev. Biophys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/humu.24004","article-title":"A mutation update for the FLNC gene in myopathies and cardiomyopathies","volume":"41","author":"Verdonschot","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Monda, E., Palmiero, G., Rubino, M., Verrillo, F., Amodio, F., Di Fraia, F., Pacileo, R., Fimiani, F., Esposito, A., and Cirillo, A. (2020). Molecular basis of inflammation in the pathogenesis of cardiomyopathies. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186462"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1016\/j.jacc.2016.09.927","article-title":"Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies","volume":"68","author":"Cuenca","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.jacep.2017.12.003","article-title":"Filamin C Truncation Mutations Are Associated With Arrhythmogenic Dilated Cardiomyopathy and Changes in the Cell\u2013Cell Adhesion Structures","volume":"4","author":"Begay","year":"2018","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/cge.13594","article-title":"FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations","volume":"96","author":"Ader","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Eden, M., and Frey, N. (2021). Cardiac Filaminopathies: Illuminating the Divergent Role of Filamin C Mutations in Human Cardiomyopathy. J. Clin. Med., 10.","DOI":"10.3390\/jcm10040577"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Celeghin, R., Cipriani, A., Bariani, R., Bueno Marinas, M., Cason, M., Bevilacqua, M., De Gaspari, M., Rizzo, S., Rigato, I., and Da Pozzo, S. (2021). Filamin-C variant-associated cardiomyopathy: A pooled analysis of individual patient data to evaluate the clinical profile and risk of sudden cardiac death. Heart Rhythm.","DOI":"10.1016\/j.hrthm.2021.09.029"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1161\/CIRCULATIONAHA.119.044061","article-title":"Loss of Filamin C Is Catastrophic for Heart Function","volume":"141","author":"Zhou","year":"2020","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1161\/CIRCRESAHA.120.317076","article-title":"Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation","volume":"129","author":"Agarwal","year":"2021","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100482","DOI":"10.1016\/j.cophys.2021.100482","article-title":"Biomechanical signals regulating the structure of the heart","volume":"25","author":"Powers","year":"2022","journal-title":"Curr. Opin. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.cell.2016.04.002","article-title":"A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy","volume":"165","author":"Davis","year":"2016","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1016\/j.bpj.2013.02.021","article-title":"Novel role for vinculin in ventricular myocyte mechanics and dysfunction","volume":"104","author":"Tangney","year":"2013","journal-title":"Biophys. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1088\/0034-4885\/69\/10\/R01","article-title":"Recent improvements in small angle x-ray diffraction for the study of muscle physiology","volume":"69","author":"Reconditi","year":"2006","journal-title":"Rep. Prog. Phys."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Williams, C.D., Regnier, M., and Daniel, T.L. (2010). Axial and radial forces of cross-bridges depend on lattice spacing. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1001018"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Williams, C.D., Regnier, M., and Daniel, T.L. (2012). Elastic energy storage and radial forces in the myofilament lattice depend on sarcomere length. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002770"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"20130697","DOI":"10.1098\/rspb.2013.0697","article-title":"The length\u2013tension curve in muscle depends on lattice spacing","volume":"280","author":"Williams","year":"2013","journal-title":"Proc. R. Soc. B Biol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1093\/icb\/icy055","article-title":"A Spatially Explicit Model Shows How Titin Stiffness Modulates Muscle Mechanics and Energetics","volume":"58","author":"Powers","year":"2018","journal-title":"Integr. Comp. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6522","DOI":"10.1128\/MCB.00243-06","article-title":"Loss of FilaminC (FLNc) Results in Severe Defects in Myogenesis and Myotube Structure","volume":"26","author":"Dalkilic","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ydbio.2011.10.008","article-title":"Filamin C plays an essential role in the maintenance of the structural integrity of cardiac and skeletal muscles, revealed by the medaka mutant zacro","volume":"361","author":"Fujita","year":"2012","journal-title":"Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Campbell, K.S. (2009). Interactions between connected half-sarcomeres produce emergent mechanical behavior in a mathematical model of muscle. PLoS Comput. Biol., 5.","DOI":"10.1371\/journal.pcbi.1000560"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"C1116","DOI":"10.1152\/ajpcell.2000.279.4.C1116","article-title":"Desmin knockout muscles generate lower stress and are less vulnerable to injury compared with wild-type muscles","volume":"279","author":"Sam","year":"2000","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"H2568","DOI":"10.1152\/ajpheart.2000.279.5.H2568","article-title":"Myofilament lattice spacing as a function of sarcomere length in isolated rat myocardium","volume":"279","author":"Irving","year":"2000","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1529\/biophysj.105.074062","article-title":"An X-Ray Diffraction Study on Mouse Cardiac Cross-Bridge Function In Vivo: Effects of Adrenergic \u03b2-Stimulation","volume":"90","author":"Toh","year":"2006","journal-title":"Biophys. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3240","DOI":"10.1073\/pnas.1619484114","article-title":"Myosin filament activation in the heart is tuned to the mechanical task","volume":"114","author":"Reconditi","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11502","DOI":"10.1073\/pnas.1905028116","article-title":"Cardiac myosin activation with 2-deoxy-ATP via increased electrostatic interactions with actin","volume":"116","author":"Powers","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","unstructured":"(2011). Guide for the Care and Use of Laboratory Animals, National Academies Press. [8th ed.]."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e142446","DOI":"10.1172\/jci.insight.142446","article-title":"Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts","volume":"5","author":"Powers","year":"2020","journal-title":"JCI Insight"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1161\/CIRCULATIONAHA.119.039751","article-title":"Nexilin Is a New Component of Junctional Membrane Complexes Required for Cardiac T-Tubule Formation","volume":"140","author":"Liu","year":"2019","journal-title":"Circulation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e138780","DOI":"10.1172\/jci.insight.138780","article-title":"Homozygous G650del nexilin variant causes cardiomyopathy in mice","volume":"5","author":"Liu","year":"2020","journal-title":"JCI Insight"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1161\/CIRCHEARTFAILURE.120.006935","article-title":"Nexilin Is Necessary for Maintaining the Transverse-Axial Tubular System in Adult Cardiomyocytes","volume":"13","author":"Spinozzi","year":"2020","journal-title":"Circ. Heart Fail."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e41378","DOI":"10.7554\/eLife.41378","article-title":"A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure","volume":"7","author":"Pollak","year":"2018","journal-title":"Elife"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1038\/s41467-021-21685-4","article-title":"Microtubules orchestrate local translation to enable cardiac growth","volume":"12","author":"Scarborough","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1161\/CIRCULATIONAHA.119.039521","article-title":"Cronos Titin Is Expressed in Human Cardiomyocytes and Necessary for Normal Sarcomere Function","volume":"140","author":"Zaunbrecher","year":"2019","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1038\/nprot.2006.203","article-title":"Micropatterned cell cultures on elastic membranes as an in vitro model of myocardium","volume":"1","author":"Camelliti","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_44","first-page":"1","article-title":"Isolation and Culture of Neonatal Mouse Cardiomyocytes","volume":"15","author":"Ehler","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/978-1-0716-1382-5_16","article-title":"Atomic Force for Live-Cell and Hydrogel Measurement","volume":"Volume 2299","author":"Whitehead","year":"2021","journal-title":"Methods in Molecular Biology"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sparrow, A.J., Sievert, K., Patel, S., Chang, Y.-F., Broyles, C.N., Brook, F.A., Watkins, H., Geeves, M.A., Redwood, C.S., and Robinson, P. (2019). Measurement of Myofilament-Localised Calcium Dynamics in Adult Cardiomyocytes and the Effect of Hypertrophic Cardiomyopathy Mutations. Circ. Res., 1228\u20131239.","DOI":"10.1161\/CIRCRESAHA.118.314600"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/S0006-3495(94)80538-7","article-title":"Passive and active tension in single cardiac myofibrils","volume":"67","author":"Linke","year":"1994","journal-title":"Biophys. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1172\/JCI61134","article-title":"Mouse and computational models link Mlc2v dephosphorylation to altered myosin kinetics in early cardiac disease","volume":"122","author":"Sheikh","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1109\/TCT.1971.1083221","article-title":"Simultaneous Numerical Solution of Differential-Algebraic Equations","volume":"18","author":"Gear","year":"1971","journal-title":"IEEE Trans. Circuit Theory"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/871\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:27:17Z","timestamp":1760362037000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/871"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,14]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23020871"],"URL":"https:\/\/doi.org\/10.3390\/ijms23020871","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,14]]}}}