@article{1b18a00e3adf4abe8e14a84b22998fb5,
title = "HDAC6 modulates myofibril stiffness and diastolic function of the heart",
abstract = "Passive stiffness of the heart is determined largely by extracellular matrix and titin, which functions as a molecular spring within sarcomeres. Titin stiffening is associated with the development of diastolic dysfunction (DD), while augmented titin compliance appears to impair systolic performance in dilated cardiomyopathy. We found that myofibril stiffness was elevated in mice lacking histone deacetylase 6 (HDAC6). Cultured adult murine ventricular myocytes treated with a selective HDAC6 inhibitor also exhibited increased myofibril stiffness. Conversely, HDAC6 overexpression in cardiomyocytes led to decreased myofibril stiffness, as did ex vivo treatment of mouse, rat, and human myofibrils with recombinant HDAC6. Modulation of myofibril stiffness by HDAC6 was dependent on 282 amino acids encompassing a portion of the PEVK element of titin. HDAC6 colocalized with Z-disks, and proteomics analysis suggested that HDAC6 functions as a sarcomeric protein deacetylase. Finally, increased myofibril stiffness in HDAC6-deficient mice was associated with exacerbated DD in response to hypertension or aging. These findings define a role for a deacetylase in the control of myofibril function and myocardial passive stiffness, suggest that reversible acetylation alters titin compliance, and reveal the potential of targeting HDAC6 to manipulate the elastic properties of the heart to treat cardiac diseases.",
author = "Lin, {Ying Hsi} and Major, {Jennifer L.} and Tim Liebner and Zaynab Hourani and Travers, {Joshua G.} and Wennersten, {Sara A.} and Haefner, {Korey R.} and Cavasin, {Maria A.} and Wilson, {Cortney E.} and Jeong, {Mark Y.} and Yu Han and Michael Gotthardt and Ferguson, {Scott K.} and Ambardekar, {Amrut V.} and Lam, {Maggie P.Y.} and Chunaram Choudhary and Granzier, {Henk L.} and Woulfe, {Kathleen C.} and McKinsey, {Timothy A.}",
note = "Funding Information: The authors acknowledge P. Buttrick, M. Bristow, and the University of Colorado Anschutz Medical Campus Division of Cardiology for ongoing maintenance of the human cardiac tissue biobank, D.C. Irwin for advice on mouse exercise testing, and J.S. Kolb for assistance with mouse colonies. YHL was supported by an American Heart Association postdoctoral fellowship (16POST30960017). JLM received funding from the Canadian Institutes of Health Research (FRN-395620). MYJ was supported by the NIH (5KL2TR001080-02), a Hartford-Jahnigen Center of Excellence in Geriatrics Pilot Grant, and a Sarnoff Endowment Fellow-to-Faculty Transition Award. AVA was supported by a Scientist Development Grant from the American Heart Association and by the Boettcher Foundation{\textquoteright}s Webb-Waring Biomedical Research Program. MPYL was funded by the NIH (R00-HL127302, R01-HL141278), and YH was supported by a postdoctoral fellowship from the NIH (F32-HL149191). The Novo Nordisk Foundation Center for Protein Research is financially supported by the Novo Nordisk Foundation (NNF14CC0001). CC was supported by a grant from the Novo Nordisk Foundation (NNF20OC0065482). HLG was funded by the National Heart, Lung, and Blood Institute (R35-HL139861). KCW received funding from the NIH (K12-HD057022 and K01-AG066845), the Lor-na Grindlay Moore Faculty Award, and the Center for Women{\textquoteright}s Health Research and SCORE Pilot Award. TAM received funding from the NIH (HL116848, HL147558, DK119594, HL127240, HL150225) and a grant from the American Heart Association (16SFRN31400013). The cardiac tissue bank utilized REDCap, which is provided by NIH/National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Award Grant UL1 TR002535. Ultrasound imaging equipment was supported by a grant from the NIH (1S1-OD018156-01). The contents of this article are solely the authors{\textquoteright} responsibility and do not necessarily represent official NIH views. Funding Information: Conflict of interest: TAM is on the scientific advisory boards of Artemes Bio and Eikonizo Therapeutics, received funding from Italfarmaco for an unrelated project, and has a subcontract from Eikonizo Therapeutics related to a Small Business Innovation Research grant from the National Institutes of Health (HL154959). Copyright: {\textcopyright} 2022, Lin et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: February 3, 2021; Accepted: April 5, 2022; Published: May 16, 2022. Reference information: J Clin Invest. 2022;132(10):e148333. https://doi.org/10.1172/JCI148333. Publisher Copyright: {\textcopyright} 2022, Lin et al.",
year = "2022",
month = may,
day = "16",
doi = "10.1172/JCI148333",
language = "English (US)",
volume = "132",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "10",
}