Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its modulation via phosphorylation

Vikhorev, Petr G.; Vikhoreva, Natalia N.; Yeung, WaiChun; Li, Amy; Lal, Sean; Remedios, Cristobal G. dos; Blair, Cheavar A.; Guglin, Maya; Campbell, Kenneth S.; Yacoub, Magdi H.; Tombe, Pieter de; Marston, Steven B.

doi:10.1093/cvr/cvaa316

Cited by 20 publications

(22 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Only eight of them had clinically diagnosed HCM based on Kuopio University Hospital medical records. We found 20 pathogenic or likely pathogenic genetic variants in the TTN gene for DCM, and almost all of them were stop codon or frameshift variants, in agreement with previously published studies [ 18 , 19 ]. Six of twenty participants had a clinical diagnosis of DCM.…”

Section: Discussionsupporting

confidence: 91%

Metabolite Signature in the Carriers of Pathogenic Genetic Variants for Cardiomyopathy: A Population-Based METSIM Study

et al. 2022

View full text Add to dashboard Cite

Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are among the leading causes of sudden cardiac death. We identified 38 pathogenic or likely pathogenic variant carriers for HCM in three sarcomere genes (MYH7, MYBPC3, TPMI) among 9.928 participants of the METSIM Study having whole exome sequencing data available. Eight of them had a clinical diagnosis of HCM. We also identified 20 pathogenic or likely pathogenic variant carriers for DCM in the TTN gene, and six of them had a clinical diagnosis of DCM. The aim of our study was to investigate the metabolite signature in the carriers of the pathogenic or likely pathogenic genetic variants for HCM and DCM, compared to age- and body-mass-index-matched controls. Our novel findings were that the carriers of pathogenic or likely pathogenic variants for HCM had significantly increased concentrations of bradykinin (des-arg 9), vanillactate, and dimethylglycine and decreased concentrations of polysaturated fatty acids (PUFAs) and lysophosphatidylcholines compared with the controls without HCM. Additionally, our novel findings were that the carriers of pathogenic or likely pathogenic variants for DCM had significantly decreased concentrations of 1,5-anhydrogluticol, histidine betaine, N-acetyltryptophan, and methylsuccinate and increased concentrations of trans-4-hydroxyproline compared to the controls without DCM. Our population-based study shows that the metabolite signature of the genetic variants for HCM and DCM includes several novel metabolic pathways not previously described.

show abstract

Section: Discussionsupporting

confidence: 91%

Metabolite Signature in the Carriers of Pathogenic Genetic Variants for Cardiomyopathy: A Population-Based METSIM Study

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In animal models, increases in interleukin-6 were associated with reduced phosphorylation of titin and cardiac dysfunction, preventable by interleukin-6 receptor blockade. 42,43 Variations in observed DCM gene prevalence between the London and Maastricht cohorts likely reflect differences in clinical presentation, although geographic differences may have influenced viral etiology and clinical course. In London, most patients with myocarditis had pseudoinfarct presentations, whereas the Maastricht cohort was accrued mainly after myocardial biopsy findings, thereby potentially biasing the sample toward those with a reduced LVEF.…”

Section: Myocarditis and Dcmmentioning

confidence: 99%

Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy

et al. 2022

View full text Add to dashboard Cite

Background: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. Methods: This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Results: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls ( P =0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P =0.001). This was driven predominantly by DSP -tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN -tv, found in 7% (all with left ventricular ejection fraction<50%) compared with 1% in controls (odds ratio, 3.6; P =0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9–7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients ( P adjusted =0.08). Conclusions: We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP -tv in those with normal left ventricular ejection fraction and TTN -tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.

show abstract

“…The former allows for assessment of titin mechanical properties (Linke et al, 1997;Makarenko et al, 2004; Opitz Vikhorev et al, 2017) whilst the latter allows measurement of length dependent activation. Such studies have confirmed that both PKA-dependent phosphorylation and titin mutations can modulate length dependent activation whist having little or no effect on baseline contractility (Vikhorev et al, 2020).…”

Section: Applicationsmentioning

confidence: 72%

“…(1) Comparing wild type with mutant muscles from transgenic mice such as the ACTC mutations E99K (HCM) and E361G (DCM) (Song et al, 2013;Vikhorev et al, 2014) or in mutant human heart myofibrils such as MYH7 R403Q, TNNT2 K280N, and titin truncating mutations (Ferrantini et al, 2009;Piroddi et al, 2019;Vikhorev et al, 2020).…”

Section: Applicationsmentioning

confidence: 99%

“…(3) The same methodology can be applied to the effects of contractile protein phosphorylation, notably by PKA, on the Ca 2+ sensitivity and relaxation kinetics (Vikhorev et al, 2014(Vikhorev et al, , 2020 and to determine the effects of myofilament targeting drugs such as Mavacamten and Omecamtiv Mecarbil (Scellini et al, 2020(Scellini et al, , 2021.…”

Section: Applicationsmentioning

confidence: 99%

See 1 more Smart Citation

Force Measurements From Myofibril to Filament

Marston

2022

Front. Physiol.

View full text Add to dashboard Cite

Contractility, the generation of force and movement by molecular motors, is the hallmark of all muscles, including striated muscle. Contractility can be studied at every level of organization from a whole animal to single molecules. Measurements at sub-cellular level are particularly useful since, in the absence of the excitation-contraction coupling system, the properties of the contractile proteins can be directly investigated; revealing mechanistic details not accessible in intact muscle. Moreover, the conditions can be manipulated with ease, for instance changes in activator Ca2+, small molecule effector concentration or phosphorylation levels and introducing mutations. Subcellular methods can be successfully applied to frozen materials and generally require the smallest amount of tissue, thus greatly increasing the range of possible experiments compared with the study of intact muscle and cells. Whilst measurement of movement at the subcellular level is relatively simple, measurement of force is more challenging. This mini review will describe current methods for measuring force production at the subcellular level including single myofibril and single myofilament techniques.

show abstract

Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its modulation via phosphorylation

Cited by 20 publications

References 81 publications

Metabolite Signature in the Carriers of Pathogenic Genetic Variants for Cardiomyopathy: A Population-Based METSIM Study

Metabolite Signature in the Carriers of Pathogenic Genetic Variants for Cardiomyopathy: A Population-Based METSIM Study

Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy

Force Measurements From Myofibril to Filament

Contact Info

Product

Resources

About