HDAC6 Modulates Myofibril Stiffness and Diastolic Function of the Heart

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2022 May 16

PMID 35575093

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 Py Lam

Chunaram Choudhary

Henk L Granzier

Kathleen C Woulfe

Timothy A McKinsey

Affiliations

Soon will be listed here.

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.

Citing Articles

VASN knockout induces myocardial fibrosis in mice by downregulating non-collagen fibers and promoting inflammation.

Sun J, Yin S, Li Q, Zhang J, Guo X, Yu N Front Pharmacol. 2025; 15:1500617.

PMID: 39898320 PMC: 11782114. DOI: 10.3389/fphar.2024.1500617.

Acetylation-Mediated Post-Translational Modification of Pyruvate Dehydrogenase Plays a Critical Role in the Regulation of the Cellular Acetylome During Metabolic Stress.

Rajakumar A, Nguyen S, Ford N, Ogundipe G, Lopez-Nowak E, Kondrachuk O Metabolites. 2024; 14(12).

PMID: 39728482 PMC: 11679536. DOI: 10.3390/metabo14120701.

Epigenetics in Heart Failure.

Ho J, Jou E, Khong P, Foo R, Sia C Int J Mol Sci. 2024; 25(22).

PMID: 39596076 PMC: 11593553. DOI: 10.3390/ijms252212010.

Integrative proteomic and metabolomic elucidation of cardiomyopathy with in vivo and in vitro models and clinical samples.

Hu Y, Zou Y, Qiao L, Lin L Mol Ther. 2024; 32(10):3288-3312.

PMID: 39233439 PMC: 11489546. DOI: 10.1016/j.ymthe.2024.08.030.

Histone deacetylase 6 controls cardiac fibrosis and remodelling through the modulation of TGF-β1/Smad2/3 signalling in post-infarction mice.

Fang J, Shu S, Dong H, Yue X, Piao J, Li S J Cell Mol Med. 2024; 28(17):e70063.

PMID: 39232846 PMC: 11374528. DOI: 10.1111/jcmm.70063.

References

Vikhorev P, Smoktunowicz N, Munster A, Copeland O, Kostin S, Montgiraud C . Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes. Sci Rep. 2017; 7(1):14829. PMC: 5665940. DOI: 10.1038/s41598-017-13675-8. View

Hopf A, Andresen C, Kotter S, Isic M, Ulrich K, Sahin S . Diabetes-Induced Cardiomyocyte Passive Stiffening Is Caused by Impaired Insulin-Dependent Titin Modification and Can Be Modulated by Neuregulin-1. Circ Res. 2018; 123(3):342-355. DOI: 10.1161/CIRCRESAHA.117.312166. View

Foster D, Liu T, Rucker J, OMeally R, DeVine L, Cole R . The cardiac acetyl-lysine proteome. PLoS One. 2013; 8(7):e67513. PMC: 3699649. DOI: 10.1371/journal.pone.0067513. View

Granzier H, Radke M, Peng J, Westermann D, Nelson O, Rost K . Truncation of titin's elastic PEVK region leads to cardiomyopathy with diastolic dysfunction. Circ Res. 2009; 105(6):557-64. PMC: 2785004. DOI: 10.1161/CIRCRESAHA.109.200964. View

Abdellatif M, Trummer-Herbst V, Koser F, Durand S, Adao R, Vasques-Novoa F . Nicotinamide for the treatment of heart failure with preserved ejection fraction. Sci Transl Med. 2021; 13(580). PMC: 7611499. DOI: 10.1126/scitranslmed.abd7064. View

Koser F, Loescher C, Linke W . Posttranslational modifications of titin from cardiac muscle: how, where, and what for?. FEBS J. 2019; 286(12):2240-2260. PMC: 6850032. DOI: 10.1111/febs.14854. View

van Heerebeek L, Hamdani N, Falcao-Pires I, Leite-Moreira A, Begieneman M, Bronzwaer J . Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012; 126(7):830-9. DOI: 10.1161/CIRCULATIONAHA.111.076075. View

Piroddi N, Belus A, Scellini B, Tesi C, Giunti G, Cerbai E . Tension generation and relaxation in single myofibrils from human atrial and ventricular myocardium. Pflugers Arch. 2006; 454(1):63-73. DOI: 10.1007/s00424-006-0181-3. View

Kruger M, Kotter S, Grutzner A, Lang P, Andresen C, Redfield M . Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ Res. 2008; 104(1):87-94. DOI: 10.1161/CIRCRESAHA.108.184408. View

10.

Guo W, Schafer S, Greaser M, Radke M, Liss M, Govindarajan T . RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat Med. 2012; 18(5):766-73. PMC: 3569865. DOI: 10.1038/nm.2693. View

11.

Lundby A, Lage K, Weinert B, Bekker-Jensen D, Secher A, Skovgaard T . Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns. Cell Rep. 2012; 2(2):419-31. PMC: 4103158. DOI: 10.1016/j.celrep.2012.07.006. View

12.

Lin Y, Schmidt W, Fritz K, Jeong M, Cammarato A, Foster D . Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity. J Mol Cell Cardiol. 2020; 139:135-147. PMC: 7363438. DOI: 10.1016/j.yjmcc.2020.01.007. View

13.

Kalin J, Bergman J . Development and therapeutic implications of selective histone deacetylase 6 inhibitors. J Med Chem. 2013; 56(16):6297-313. DOI: 10.1021/jm4001659. View

14.

Granzier H, Irving T . Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys J. 1995; 68(3):1027-44. PMC: 1281826. DOI: 10.1016/S0006-3495(95)80278-X. View

15.

Lemon D, Horn T, Cavasin M, Jeong M, Haubold K, Long C . Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension. J Mol Cell Cardiol. 2011; 51(1):41-50. PMC: 3113526. DOI: 10.1016/j.yjmcc.2011.04.005. View

16.

Lahmers S, Wu Y, Call D, Labeit S, Granzier H . Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ Res. 2004; 94(4):505-13. DOI: 10.1161/01.RES.0000115522.52554.86. View

17.

Matsuyama A, Shimazu T, Sumida Y, Saito A, Yoshimatsu Y, Seigneurin-Berny D . In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J. 2002; 21(24):6820-31. PMC: 139102. DOI: 10.1093/emboj/cdf682. View

18.

Liss M, Radke M, Eckhard J, Neuenschwander M, Dauksaite V, von Kries J . Drug discovery with an RBM20 dependent titin splice reporter identifies cardenolides as lead structures to improve cardiac filling. PLoS One. 2018; 13(6):e0198492. PMC: 5995442. DOI: 10.1371/journal.pone.0198492. View

19.

Fraysse B, Weinberger F, Bardswell S, Cuello F, Vignier N, Geertz B . Increased myofilament Ca2+ sensitivity and diastolic dysfunction as early consequences of Mybpc3 mutation in heterozygous knock-in mice. J Mol Cell Cardiol. 2012; 52(6):1299-307. PMC: 3370652. DOI: 10.1016/j.yjmcc.2012.03.009. View

20.

Zou H, Wu Y, Navre M, Sang B . Characterization of the two catalytic domains in histone deacetylase 6. Biochem Biophys Res Commun. 2006; 341(1):45-50. DOI: 10.1016/j.bbrc.2005.12.144. View