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Cited by 5Cardiomyopathy and Myosin StudiesCardiac Fibrosis and RemodelingCongenital heart defects research

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Nonmuscle α-Actinin-4 Couples Sarcomere Function to Cardiac Remodeling

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Hayes, James B., Choudhary, Dharmendra, Ritter, Dylan, Neininger-Castro, Abigail C., Willet, Alaina H., Caplan, Leah R., Wang, Yu, Liu, Xiao, Taneja, Nilay, Sanchez, Zachary C., Smart, Kyra, Armstrong, David W.J., Reinhart-King, Cynthia A., Liu, Qi, Tyska, Matthew J., Tabdanov, Erdem D., Merryman, W. David, Wells, Quinn S., Knapik, Ela W., Burnette, Dylan T.·2026·Circulation Research
DOI 10.1161/circresaha.125.326412PMC PMC12757129

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Abstract

BACKGROUND: Cardiac sarcomeres generate the fundamental forces of each heartbeat. Cardiac myocytes (CMs) express nonmuscle versions of muscle-specific sarcomere proteins, which have unknown relevance to sarcomere function or heart physiology. METHODS: Expression levels of nonmuscle cytoskeletal proteins versus muscle-specific counterparts in CMs were directly compared. Function and subcellular localization of the nonmuscle protein ACTN4 (alpha-actinin-4) in induced pluripotent stem cell–derived CMs were determined using small interfering RNA–mediated knockdown, overexpression, and pharmacological perturbation. Impacts of ACTN4 depletion or knockout on cardiac structure function were evaluated in zebrafish embryos. Left ventricular Actn4 expression was evaluated in a mouse model of chronic pressure overload. Human ACTN4 gene variants were tested for association with heart failure with preserved ejection fraction using the BioVU biobank. A meta-analysis was conducted on ventricular data sets of human cardiomyopathies. RESULTS: ACTN4 expression in human CMs met or exceeded some muscle-specific genes (eg, MYH6 ). Anti-ACTN4 antibodies colocalized with anti-ACTN2 (alpha-actinin-2) at the sarcomere Z-disc in human, mouse, and zebrafish ventricular tissue. Coimmunoprecipitation and structural modeling suggest a Z-disc ACTN4:ACTN2 complex. ACTN4 depletion from induced pluripotent stem cell–derived CMs resulted in increased sarcomere assembly, decreased sarcomere component turnover, elevated contractile force, and contractility-dependent cellular hypertrophy. Overexpression of an ACTN4 actin-binding chimera suppressed sarcomere assembly. In zebrafish embryos, ACTN4 depletion/knockout induced ventricular hypercontractility and atrial enlargement. Selective modulation of ventricular contractility was sufficient to prevent or phenocopy atrial remodeling. In mice, Actn4 , but not Actn2 , was upregulated in the left ventricular following pressure overload. One of 14 ACTN4 single-nucleotide polymorphisms was associated with reduced heart failure with preserved ejection fraction risk in humans, and prepublished studies suggest a pattern of ventricular ACTN4 upregulation in certain human cardiomyopathies. CONCLUSIONS: A nonmuscle actinin (ACTN4) populates the cardiac Z-disc. ACTN4 regulates sarcomeric architecture in CMs. ACTN4 influences fractional shortening at the cell level and contractility at the tissue level. Changes in ventricular ACTN4 levels are associated with remodeling and may influence clinical outcomes related to heart failure.

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Metadata

Authors
Hayes, J. B., Choudhary, D., Ritter, D., Neininger-Castro, A. C., Willet, A. H., Caplan, L. R., Wang, Y., Liu, X., Taneja, N., Sanchez, Z. C., Smart, K., Armstrong, D. W. J., Reinhart-King, C. A., Liu, Q., Tyska, M. J., Tabdanov, E. D., Merryman, W. D., Wells, Q. S., Knapik, E. W., & Burnette, D. T.
Affiliations
  • Vanderbilt University (US)
  • Vanderbilt University Medical Center (US)
  • Department of Cell and Developmental Biology, Vanderbilt University School of Medicine Basic Sciences, Nashville, TN (J.B.H., D.R., A.C.N.-C., A.H.W., L.R.C., N.T., Z.C.S., M.J.T., E.W.K., D.T.B.).
  • Department of Biomedical Engineering, Vanderbilt University, Nashville, TN (K.S., C.A.R.-K., W.D.M.).
  • Pennsylvania State University (US)
Corresponding author
Burnette, Dylan T.
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2026-01-02
Volume
138
Issue
1
Pages
e326412-e326412
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.125.326412
PMC
PMC12757129
OpenAlex
W4416393108
Cited by
5
References
3
Citations by year
2026: 5
FWCI
3.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Circulation Research (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
Funders
  • National Institute of General Medical Sciences (R35GM125028)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK101003)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Keywords
ACTN4, non-muscle actin, cardiac sarcomere, sarcomere assembly, Z-disc, ACTN2, cardiac remodeling, ventricular hypertrophy, cardiac contractility, atrial remodeling, pressure overload, heart failure with preserved ejection fraction, cardiomyopathy, single nucleotide polymorphisms, iPSC-derived cardiomyocytes, zebrafish embryos
MeSH terms
Actinin, Animals, Cells, Cultured, Heart Failure, Humans, Male, Sarcomeres, Zebrafish, Mice, Knockout, Ventricular Remodeling, Myocytes, Cardiac, Mice, Induced Pluripotent Stem Cells

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