HDAC6 modulates myofibril stiffness and diastolic function of the heart
Ying-Hsi Lin, Jennifer L. Major, Tim Liebner, Zaynab Hourani, Joshua G. Travers, Sara A. Wennersten, Korey R. Haefner, Maria A. Cavasin, Cortney E. Wilson, Mark Y. Jeong, Yu Han, Michael Gotthardt, Scott K. Ferguson, Amrut V. Ambardekar, Maggie P.Y. Lam, Chunaram Choudhary, Henk L. Granzier, Kathleen C. Woulfe, Timothy A. McKinsey
Ying-Hsi Lin, Jennifer L. Major, Tim Liebner, Zaynab Hourani, Joshua G. Travers, Sara A. Wennersten, Korey R. Haefner, Maria A. Cavasin, Cortney E. Wilson, Mark Y. Jeong, Yu Han, Michael Gotthardt, Scott K. Ferguson, Amrut V. Ambardekar, Maggie P.Y. Lam, Chunaram Choudhary, Henk L. Granzier, Kathleen C. Woulfe, Timothy A. McKinsey
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Research Article Cardiology

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.

Authors

Ying-Hsi Lin, Jennifer L. Major, Tim Liebner, Zaynab Hourani, Joshua G. Travers, Sara A. Wennersten, Korey R. Haefner, Maria A. Cavasin, Cortney E. Wilson, Mark Y. Jeong, Yu Han, Michael Gotthardt, Scott K. Ferguson, Amrut V. Ambardekar, Maggie P.Y. Lam, Chunaram Choudhary, Henk L. Granzier, Kathleen C. Woulfe, Timothy A. McKinsey

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Figure 4

Recombinant HDAC6 regulates myofibril stiffness in a manner that is dependent on a region of titin encompassing a portion of the PEVK element and an adjacent Ig-like domain.

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Recombinant HDAC6 regulates myofibril stiffness in a manner that is depe...
(A) Schematic representation of the ex vivo assay using recombinant HDACs and myofibrils isolated from rat or human left ventricles (LVs). (B and C) Myofibril resting tension–to–sarcomere length curves. (D) Schematic representation of the ex vivo assay using myofibrils from WT and PEVK/Ig-like domain–KO mouse LVs. (E and F) Myofibril resting tension–to–sarcomere length curves. (G) Schematic representation of the experiment using cultured adult mouse ventricular myocytes (AMVMs) from WT and PEVK-KO mice. (H) Myofibril resting tension (mN/mm2) at a sarcomere length of 2.0–2.2 μm. (I) Myofibril resting tension–to–sarcomere length curves. For B, C, E, F, and I, data are presented as mean ± SEM, fitted by third-order polynomials. For E, F, H, and I, 6–8 myofibrils from 3 mice per group (WT and KO) were analyzed. For H, mean + SEM is shown; *P < 0.05 vs. WT + vehicle based on 1-way ANOVA with Tukey’s multiple-comparison test.