Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

Jeong, Mark Y.; Lin, Ying; Wennersten, Sara A.; Demos-Davies, Kimberly M; Cavasin, Maria A.; Mahaffey, Jennifer; Monzani, V.; Saripalli, Chandrasekhar; Mascagni, Paolo; Reece, T. Brett; Ambardekar, Amrut V.; Granzier, Henk; Dinarello, Charles A.; McKinsey, Timothy A.

doi:10.1126/scitranslmed.aao0144

Cited by 126 publications

(121 citation statements)

References 42 publications

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“…There are 2 families of enzymes that regulate acetylation: lysine acetyl transferases (KATs, also known as histone acetyltransferases) reversibly acetylate lysine, and lysine deacetylases (KDACs, also known as histone deacetylases) remove acetyl groups from lysines. While the identity of the sarcomeric KATs and KDACs, as well as their target-site specificity, have yet to be determined, Jeong et al (2018) recently demonstrated that myofibrils treated, ex vivo, with p300 (a promiscuous acetyltransferase), increased sarcomeric acetylation and accelerated relaxation [14]. Thus, sarcomeric acetylation is sufficient to modulate contractile dynamics, though the precise sarcomeric acetylation sites that can impact myofilament contractility have not been determined.…”

Section: Introductionmentioning

confidence: 99%

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity

Lin

Schmidt

Fritz

et al. 2020

Journal of Molecular and Cellular Cardiology

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Cardiac troponin I (cTnI) is an essential physiological and pathological regulator of cardiac relaxation. Significant to this regulation, the post-translational modification of cTnI through phosphorylation functions as a key mechanism to accelerate myofibril relaxation. Similar to phosphorylation, post-translational modification by acetylation alters amino acid charge and protein function. Recent studies have demonstrated that the acetylation of cardiac myofibril proteins accelerates relaxation and that cTnI is acetylated in the heart. These findings highlight the potential significance of myofilament acetylation; however, it is not known if site-specific acetylation of cTnI can lead to changes in myofilament, myofibril, and/or cellular mechanics. The objective of this study was to determine the effects of mimicking acetylation at a single site of cTnI (lysine-132; K132) on myofilament, myofibril, and cellular mechanics and elucidate its influence on molecular function. Methods: To determine if pseudo-acetylation of cTnI at 132 modulates thin filament regulation of the actomyosin interaction, we reconstituted thin filaments containing WT or K132Q (to mimic acetylation) cTnI and assessed in vitro motility. To test if mimicking acetylation at K132 alters cellular relaxation, adult rat ventricular cardiomyocytes were infected with adenoviral constructs expressing either cTnI K132Q or K132 replaced with arginine (K132R; to prevent acetylation) and cell shortening and isolated myofibril mechanics were measured. Finally, to confirm that changes in cell shortening and myofibril mechanics were directly due to pseudo-acetylation of cTnI at K132, we exchanged troponin containing WT or K132Q cTnI into isolated myofibrils and measured myofibril mechanical properties. Results: Reconstituted thin filaments containing K132Q cTnI exhibited decreased calcium sensitivity compared to thin filaments reconstituted with WT cTnI. Cardiomyocytes expressing K132Q cTnI had faster relengthening and myofibrils isolated from these cells had faster relaxation along with decreased calcium sensitivity compared to cardiomyocytes expressing WT or K132R cTnI. Myofibrils exchanged with K132Q cTnI ex vivo demonstrated faster relaxation and decreased calcium sensitivity. Conclusions: Our results indicate for the first time that mimicking acetylation of a specific cTnI lysine accelerates myofilament, myofibril, and myocyte relaxation. This work underscores the importance of understanding how acetylation of specific sarcomeric proteins affects cardiac homeostasis and disease and suggests that modulation of myofilament lysine acetylation may represent a novel therapeutic target to alter cardiac relaxation.

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Section: Introductionmentioning

confidence: 99%

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity

Lin

Schmidt

Fritz

et al. 2020

Journal of Molecular and Cellular Cardiology

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“…Control hearts were obtained from unused donor hearts that could not be used for transplantation. Myofibril mechanics were quantified using the fast solution switching technique (38). Details are provided in SI Appendix, Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

LAMP-2B regulates human cardiomyocyte function by mediating autophagosome–lysosome fusion

Chi

Leonard

Knight

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in lysosomal-associated membrane protein 2 (LAMP-2) gene are associated with Danon disease, which often leads to cardiomyopathy/heart failure through poorly defined mechanisms. Here, we identify the LAMP-2 isoform B (LAMP-2B) as required for autophagosome–lysosome fusion in human cardiomyocytes (CMs). Remarkably, LAMP-2B functions independently of syntaxin 17 (STX17), a protein that is essential for autophagosome–lysosome fusion in non-CMs. Instead, LAMP-2B interacts with autophagy related 14 (ATG14) and vesicle-associated membrane protein 8 (VAMP8) through its C-terminal coiled coil domain (CCD) to promote autophagic fusion. CMs derived from induced pluripotent stem cells (hiPSC-CMs) from Danon patients exhibit decreased colocalization between ATG14 and VAMP8, profound defects in autophagic fusion, as well as mitochondrial and contractile abnormalities. This phenotype was recapitulated by LAMP-2B knockout in non-Danon hiPSC-CMs. Finally, gene correction of LAMP-2 mutation rescues the Danon phenotype. These findings reveal a STX17-independent autophagic fusion mechanism in human CMs, providing an explanation for cardiomyopathy in Danon patients and a foundation for targeting defective LAMP-2B–mediated autophagy to treat this patient population.

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“…Myofibrils were isolated from flash frozen soleus and tibialis anterior as described (35,36). A small section of muscle was cut into thin slices and bathed in 0.05% Triton X-100…”

Section: Myofibril Isolationmentioning

confidence: 99%

“…Myofibrils were isolated and mechanical parameters were measured as described (36)(37)(38). Myofibrils were placed on a glass coverslip in relaxing solution at 15°C and then a small bundle of myofibrils was mounted on two microtools.…”

Section: Myofibril Mechanicsmentioning

confidence: 99%

Novel model of distal myopathy caused by the myosin rod mutation R1500P disrupts acto-myosin binding

Wilson

Buvoli

et al. 2019

Preprint

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Introduction: More than 400 mutations in β-myosin, a slow myosin motor, can cause both cardiac and skeletal myopathy in humans. A small subset of these mutations, mostly located in the myosin rod, leads to a progressive skeletal muscle disease known as Laing distal myopathy (MPD1). While this disease has previously been studied using a variety of systems, it has never been studied in the mammalian muscle environment. Here, we describe a mouse model for the MPD1-causing mutation R1500P to elucidate disease pathogenesis and to act as a future platform for testing therapeutic interventions.Methods: Because mice have very few slow skeletal muscles compared to humans, we generated mice expressing the β-myosin R1500P mutation or WT β-myosin in fast skeletal muscle fibers and determined the structural and functional consequences of the R1500P mutation. Results:The mutant R1500P myosin affects both muscle histological structure and function and the mice exhibit a number of the histological hallmarks that are often identified in patients with MPD1. Furthermore, R1500P mice show decreased muscle strength and endurance, as well as ultrastructural abnormalities in the SR & t-tubules.Somewhat surprisingly because of its location in the rod, the R1500P mutation weakens acto-myosin binding by affecting cross-bridge detachment rate. Conclusions:While each group of MPD1-causing mutations most likely operates through distinct mechanisms, our model provides new insight into how a mutation in the rod domain impacts muscle structure and function and leads to disease.

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Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

Cited by 126 publications

References 42 publications

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity

LAMP-2B regulates human cardiomyocyte function by mediating autophagosome–lysosome fusion

Novel model of distal myopathy caused by the myosin rod mutation R1500P disrupts acto-myosin binding

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