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Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients.

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of HCM patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated a cardiovascular-mutant medaka fish, non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and expressed pathologically stiffer titin isoforms. In addition, the nsh heterozygotes showed M-line disassembly that is similar to the pathological changes found in HCM. Positional cloning revealed a missense mutation in an immunoglobulin (Ig) domain located in the M-line-A-band transition zone of titin. Screening of mutations in 96 unrelated patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M-line region of titin. In vitro studies revealed that the mutations found both in medaka fish and in familial HCM increased binding of titin to muscle-specific ring finger protein 1 (MURF1) and enhanced titin degradation by ubiquitination. These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM.

SUBMITTER: Higashikuse Y

PROVIDER: S-EPMC6899042 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients.

Higashikuse Yuta Y Mittal Nishant N Arimura Takuro T Yoon Sung Han SH Oda Mayumi M Enomoto Hirokazu H Kaneda Ruri R Hattori Fumiyuki F Suzuki Takeshi T Kawakami Atsushi A Gasch Alexander A Furukawa Tetsushi T Labeit Siegfried S Fukuda Keiichi K Kimura Akinori A Makino Shinji S

Disease models & mechanisms 20191115 11

Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of HCM patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated a cardiovascular-mutant medaka fish, non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh< ...[more]

PMID: 31628103

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Project description:The giant protein titin performs structure-preserving functions in the sarcomere and is important for the passive stiffness (Fpassive) of cardiomyocytes. Protein kinase D (PKD) enzymes play crucial roles in regulating myocardial contraction, hypertrophy, and remodeling. PKD phosphorylates myofilament proteins, but it is not known whether the giant protein titin is also a PKD substrate. Here, we aimed to determine whether PKD phosphorylates titin and thereby modulates cardiomyocyte Fpassive in normal and failing myocardium. The phosphorylation of titin was assessed in cardiomyocyte-specific PKD knock-out mice (cKO) and human hearts using immunoblotting with a phosphoserine/threonine and a phosphosite-specific titin antibody. PKD-dependent site-specific titin phosphorylation in vivo was quantified by mass spectrometry using stable isotope labeling by amino acids in cell culture (SILAC) of SILAC-labeled mouse heart protein lysates that were mixed with lysates isolated from hearts of either wild-type control (WT) or cKO mice. Fpassive of single permeabilized cardiomyocytes was recorded before and after PKD and HSP27 administration. All-titin phosphorylation was reduced in cKO compared to WT hearts. Multiple conserved PKD-dependent phosphosites were identified within the Z-disk, A-band and M-band regions of titin by quantitative mass spectrometry, and many PKD-dependent phosphosites detected in the elastic titin I-band region were significantly decreased in cKO. Analysis of titin site-specific phosphorylation showed unaltered or upregulated phosphorylation in cKO compared to matched WT hearts. Fpassive was elevated in cKO compared to WT cardiomyocytes and PKD administration lowered Fpassive of WT and cKO cardiomyocytes. Cardiomyocytes from hypertrophic cardiomyopathy (HCM) patients showed higher Fpassive compared to control hearts and significantly lower Fpassive after PKD treatment. In addition, we found higher phosphorylation at CaMKII-dependent titin sites in HCM compared to control hearts. Expression and phosphorylation of HSP27, a substrate of PKD, were elevated in HCM hearts, which was associated with increased PKD expression and phosphorylation. The relocalization of HSP27 in HCM away from the sarcomeric Z-disk and I-band suggested that HSP27 failed to exert its protective action on titin extensibility. This protection could, however, be restored by administration of HSP27, which significantly reduced Fpassive in HCM cardiomyocytes. These findings establish a previously unknown role for PKDin regulating diastolic passive properties of healthy and diseased hearts.

Project description:BackgroundThe clinical presentation and prognosis of hypertrophic cardiomyopathy (HCM) are heterogeneous between nonobstructive HCM (HNCM) and obstructive HCM (HOCM). Electrocardiography (ECG) has been used as a screening tool for HCM. However, it is still unclear whether the features presented on ECG could be used for the initial classification of HOCM and HNCM.ObjectiveWe aimed to develop a pragmatic model based on common 12-lead ECG features for the initial identification of HOCM/HNCM.MethodsBetween April 1st and September 30th, 2020, 172 consecutive HCM patients from the International Cooperation Center for Hypertrophic Cardiomyopathy of Xijing Hospital were prospectively included in the training cohort. Between January 4th and February 30th, 2021, an additional 62 HCM patients were prospectively included in the temporal internal validation cohort. External validation was performed using retrospectively collected ECG data with definite classification (390 HOCM and 499 HNCM ECG samples) from January 1st, 2010 to March 31st, 2020. Multivariable backward logistic regression (LR) was used to develop the prediction model. The discrimination performance, calibration and clinical utility of the model were evaluated.ResultsOf all 30 acquired ECG parameters, 10 variables were significantly different between HOCM and HNCM (all P < 0.05). The P wave interval and SV1 were selected to construct the model, which had a clearly useful C-statistic of 0.805 (0.697, 0.914) in the temporal validation cohort and 0.776 (0.746, 0.806) in the external validation cohort for differentiating HOCM from HNCM. The calibration plot, decision curve analysis, and clinical impact curve indicated that the model had good fitness and clinical utility.ConclusionThe pragmatic model constructed by the P wave interval and SV1 had a clearly useful ability to discriminate HOCM from HNCM. The model might potentially serve as an initial classification of HCM before referring patients to dedicated centers and specialists.HighlightsWhat are the novel findings of this work? Evident differences exist in the ECG presentations between HOCM and HNCM.To the best of our knowledge, this study is the first piece of evidence to quantify the difference in the ECG presentations between HOCM and HNCM.Based on routine 12-lead ECG data, a probabilistic model was generated that might assist in the initial classification of HCM patients.

Dataset Information

Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients.

Publications

Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients.

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