-
Protein & Cell May 2024Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is characterized by primary left ventricular hypertrophy usually caused by mutations in...
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is characterized by primary left ventricular hypertrophy usually caused by mutations in sarcomere genes. The mechanism underlying cardiac remodeling in HCM remains incompletely understood. An investigation of HCM through integrative analysis at multi-omics levels will be helpful for treating HCM. DNA methylation and chromatin accessibility, as well as gene expression, were assessed by nucleosome occupancy and methylome sequencing (NOMe-seq) and RNA-seq, respectively, using the cardiac tissues of HCM patients. Compared with those of the controls, the transcriptome, DNA methylome and chromatin accessibility of the HCM myocardium showed multifaceted differences. At the transcriptome level, HCM hearts returned to the fetal gene program through decreased sarcomeric and metabolic gene expression and increased extracellular matrix gene expression. In the DNA methylome, hypermethylated and hypomethylated differentially methylated regions (DMRs) were identified in HCM. At the chromatin accessibility level, HCM hearts showed changes in different genome elements. Several transcription factors (TFs), including SP1 and EGR1, exhibited a fetal-like pattern of binding motifs in nucleosome-depleted regions (NDRs) in HCM. In particular, the inhibition of SP1 or EGR1 in an HCM mouse model harboring sarcomere mutations markedly alleviated the HCM phenotype of the mutant mice and reversed fetal gene reprogramming. Overall, this study not only provides a high precision multi-omics map of HCM heart tissue but also sheds light on the therapeutic strategy by intervening the fetal gene reprogramming in HCM.
PubMed: 38780967
DOI: 10.1093/procel/pwae032 -
Journal of Texture Studies Jun 2024Texture deterioration of meat products upon high-temperature sterilization is a pressing issue in the meat industry. This study evaluated the effect of different thermal...
Insight into the evolution of textural properties and juiciness of ready-to-eat chicken breasts upon different thermal sterilization: From the perspective of protein degradation.
Texture deterioration of meat products upon high-temperature sterilization is a pressing issue in the meat industry. This study evaluated the effect of different thermal sterilization temperatures on the textural and juiciness of ready-to-eat (RTE) chicken breast. In this study, by dynamically monitoring the texture and juiciness of chicken meat products during the process of thermal sterilization, it has been observed that excessively high sterilization temperatures (above 100°C) significantly diminish the shear force, springiness and water-holding capacity of the products. Furthermore, from the perspective of myofibrillar protein degradation, molecular mechanisms have been elucidated, unveiling that the thermal sterilization treatment at 121°C/10 min triggers the degradation of myosin heavy chains and F-actin, disrupting the lattice arrangement of myofilaments, compromising the integrity of sarcomeres, and resulting in an increase of approximately 40.66% in the myofibrillar fragmentation index, thus diminishing the quality characteristics of the products. This study unravels the underlying mechanisms governing the dynamic changes in quality of chicken meat products during the process of thermal sterilization, thereby providing theoretical guidance for the development of high-quality chicken products.
Topics: Animals; Chickens; Sterilization; Hot Temperature; Meat Products; Food Handling; Proteolysis; Meat; Actins; Myofibrils; Muscle Proteins
PubMed: 38778604
DOI: 10.1111/jtxs.12835 -
The effect of muscle ultrastructure on the force, displacement and work capacity of skeletal muscle.Journal of the Royal Society, Interface May 2024Skeletal muscle powers animal movement through interactions between the contractile proteins, actin and myosin. Structural variation contributes greatly to the variation...
Skeletal muscle powers animal movement through interactions between the contractile proteins, actin and myosin. Structural variation contributes greatly to the variation in mechanical performance observed across muscles. In vertebrates, gross structural variation occurs in the form of changes in the muscle cross-sectional area : fibre length ratio. This results in a trade-off between force and displacement capacity, leaving work capacity unaltered. Consequently, the maximum work per unit volume-the work density-is considered constant. Invertebrate muscle also varies in muscle ultrastructure, i.e. actin and myosin filament lengths. Increasing actin and myosin filament lengths increases force capacity, but the effect on muscle fibre displacement, and thus work, capacity is unclear. We use a sliding-filament muscle model to predict the effect of actin and myosin filament lengths on these mechanical parameters for both idealized sarcomeres with fixed actin : myosin length ratios, and for real sarcomeres with known filament lengths. Increasing actin and myosin filament lengths increases stress without reducing strain capacity. A muscle with longer actin and myosin filaments can generate larger force over the same displacement and has a higher work density, so seemingly bypassing an established trade-off. However, real sarcomeres deviate from the idealized length ratio suggesting unidentified constraints or selective pressures.
Topics: Animals; Muscle, Skeletal; Models, Biological; Myosins; Muscle Contraction; Actins; Sarcomeres; Biomechanical Phenomena
PubMed: 38774960
DOI: 10.1098/rsif.2023.0658 -
ESC Heart Failure May 2024Hypertrophic cardiomyopathy (HCM) due to thick filament variants is more common; however, HCM due to thin filament variants (HCM-Thin) may be associated with a more... (Review)
Review
Hypertrophic cardiomyopathy (HCM) due to thick filament variants is more common; however, HCM due to thin filament variants (HCM-Thin) may be associated with a more malignant phenotype with an increased risk of sudden cardiac death. The aim of this study was to review all the published cases of HCM-Thin to better understand the natural history and clinical outcomes of this disease. A literature review of HCM-Thin identified 21 studies with a total of 177 patients that were suitable for analysis. There were three outcomes of interest, which included a heart failure composite, a ventricular arrhythmia composite and a heart failure and arrhythmia composite outcome. Kaplan-Meier (KM) survival analyses for freedom from each of the abovementioned composite outcomes were completed for the entire cohort and stratified by age of onset and sarcomeric variant. The heart failure composite occurred in 24 (13.6%) patients, the ventricular arrhythmia composite occurred in 30 patients (16.9%) and the combined heart failure and arrhythmia composite occurred in 50 patients (28.2%). In regard to left ventricular ejection fraction (LVEF), the majority of patients were preserved (LVEF > 50%) compared with mildly reduced (LVEF 41%-50%) and reduced (LVEF ≤ 40%) (respectively 26.6% vs. 0.6% vs. 3.4%). The median maximal left ventricular wall thickness (LVWT) was 19.0 mm [interquartile range (IQR) 5.3]. Only 10.7% of the cohort had evidence of left ventricular outflow tract (LVOT) obstruction. Those with paediatric-onset HCM had earlier onset and were at higher risk for each endpoint than their adult counterparts. When stratified by genetic variant, patients with TNNI3 and TPM1 were at a higher risk of the heart failure composite endpoint and the combined heart failure and arrhythmia composite endpoint in comparison with those with the other genetic variants. HCM-Thin is associated with significant morbidity and mortality, with a high arrhythmia burden despite low rates of cardiac obstruction and mild hypertrophy. The paediatric onset of disease and certain sarcomeric variants appear to be associated with a worse prognosis than their adult-onset and other sarcomeric variant counterparts. HCM-Thin seems to have a distinct phenotype, which may require a different management approach.
PubMed: 38773858
DOI: 10.1002/ehf2.14848 -
Advanced Healthcare Materials May 2024Here an electrical stimulation system is described for maturing microfiber-shaped cardiac tissue (cardiac microfibers, CMFs). The system enables stable culturing of CMFs...
Here an electrical stimulation system is described for maturing microfiber-shaped cardiac tissue (cardiac microfibers, CMFs). The system enables stable culturing of CMFs with electrical stimulation by placing the tissue between electrodes. The electrical stimulation device provides an electric field covering whole CMFs within the stimulation area and can control the beating of the cardiac microfibers. In addition, CMFs under electrical stimulation with different frequencies are examined to evaluate the maturation levels by their sarcomere lengths, electrophysiological characteristics, and gene expression. Sarcomere elongation (14% increase compared to control) is observed at day 10, and a significant upregulation of electrodynamic properties such as gap junction protein alpha 1 (GJA1) and potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) (maximum fourfold increase compared to control) is observed at day 30. These results suggest that electrically stimulated cultures can accelerate the maturation of microfiber-shaped cardiac tissues compared to those without electrical stimulation. This model will contribute to the pathological research of unexplained cardiac diseases and pharmacologic testing by stably constructing matured CMFs.
PubMed: 38768494
DOI: 10.1002/adhm.202303477 -
BioRxiv : the Preprint Server For... Jun 2024Cardiomyopathies, often caused by mutations in genes encoding muscle proteins, are traditionally treated by phenotyping hearts and addressing symptoms post irreversible...
UNLABELLED
Cardiomyopathies, often caused by mutations in genes encoding muscle proteins, are traditionally treated by phenotyping hearts and addressing symptoms post irreversible damage. With advancements in genotyping, early diagnosis is now possible, potentially preventing such damage. However, the intricate structure of muscle and its myriad proteins make treatment predictions challenging. Here we approach the problem of estimating therapeutic targets for a mutation in mouse muscle using a spatially explicit half sarcomere muscle model. We selected 9 rate parameters in our model linked to both small molecules and cardiomyopathy-causing mutations. We then randomly varied these rate parameters and simulated an isometric twitch for each combination to generate a large training dataset. We used this dataset to train a Conditional Variational Autoencoder (CVAE), a technique used in Bayesian parameter estimation. Given simulated or experimental isometric twitches, this machine learning model is able to then predict the set of rate parameters which are most likely to yield that result. We then predict the set of rate parameters associated with both control and the cardiac Troponin C (cTnC) I61Q variant in mouse trabeculae and model parameters that recover the abnormal I61Q cTnC twitches.
SIGNIFICANCE
Machine learning techniques have potential to accelerate discoveries in biologically complex systems. However, they require large data sets and can be challenging in high dimensional systems such as cardiac muscle. In this study, we combined experimental measures of cardiac muscle twitch forces with mechanistic simulations and a newly developed mixture of Bayesian inference with neural networks (in autoencoders) to solve the inverse problem of determining the underlying kinetics for observed force generation by cardiac muscle. The autoencoders are trained on millions of simulations spanning parameter spaces that correspond to the mechanochemistry of cardiac sarcomeres. We apply the trained model to experimental data in order to infer parameters that can explain a diseased twitch and ways to recover it.
PubMed: 38766103
DOI: 10.1101/2024.05.08.593035 -
Human Cell Jul 2024Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the MYPBC3 gene, which encodes the cardiac myosin-binding protein C (cMyBP-C). Most pathogenic...
Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the MYPBC3 gene, which encodes the cardiac myosin-binding protein C (cMyBP-C). Most pathogenic variants in MYPBC3 are either nonsense mutations or result in frameshifts, suggesting that the primary disease mechanism involves reduced functional cMyBP-C protein levels within sarcomeres. However, a subset of MYPBC3 variants are missense mutations, and the molecular mechanisms underlying their pathogenicity remain elusive. Upon in vitro differentiation into cardiomyocytes, induced pluripotent stem cells (iPSCs) derived from HCM patients represent a valuable resource for disease modeling. In this study, we generated two iPSC lines from peripheral blood mononuclear cells (PBMCs) of a female with early onset and severe HCM linked to the MYBPC3: c.772G > A variant. Although this variant was initially classified as a missense mutation, recent studies indicate that it interferes with splicing and results in a frameshift. The generated iPSC lines exhibit a normal karyotype and display hallmark characteristics of pluripotency, including the ability to undergo trilineage differentiation. These novel iPSCs expand the existing repertoire of MYPBC3-mutated cell lines, broadening the spectrum of resources for exploring how diverse mutations induce HCM. They additionally offer a platform to study potential secondary genetic elements contributing to the pronounced disease severity observed in this individual.
Topics: Humans; Induced Pluripotent Stem Cells; Cardiomyopathy, Hypertrophic; Female; Carrier Proteins; Cell Differentiation; Myocytes, Cardiac; Mutation, Missense; Severity of Illness Index; Mutation; Cell Line; Frameshift Mutation; Leukocytes, Mononuclear; Cells, Cultured
PubMed: 38762696
DOI: 10.1007/s13577-024-01073-y -
Archives of Cardiovascular Diseases 2024The efficacy of current pharmacological therapies in hypertrophic cardiomyopathy is limited. A cardiac myosin inhibitor, mavacamten, has recently been approved as a...
Target population for a selective cardiac myosin inhibitor in hypertrophic obstructive cardiomyopathy: Real-life estimation from the French register of hypertrophic cardiomyopathy (REMY).
BACKGROUND
The efficacy of current pharmacological therapies in hypertrophic cardiomyopathy is limited. A cardiac myosin inhibitor, mavacamten, has recently been approved as a first-in-class treatment for symptomatic hypertrophic obstructive cardiomyopathy.
AIMS
To assess the profile and burden of cardiac myosin inhibitor candidates in the hypertrophic cardiomyopathy prospective Register of hypertrophic cardiomyopathy (REMY) held by the French Society of Cardiology.
METHODS
Data were collected at baseline and during follow-up from patients with hypertrophic cardiomyopathy enrolled in REMY by the three largest participating centres.
RESULTS
Among 1059 adults with hypertrophic cardiomyopathy, 461 (43.5%) had obstruction; 325 (30.7%) of these were also symptomatic, forming the "cardiac myosin inhibitor candidates" group. Baseline features of this group were: age 58±15years; male sex (n=196; 60.3%); diagnosis-to-inclusion delay 5 (1-12)years; maximum wall thickness 20±6mm; left ventricular ejection fraction 69±6%; family history of hypertrophic cardiomyopathy or sudden cardiac death (n=133; 40.9%); presence of a pathogenic sarcomere gene mutation (n=101; 31.1%); beta-blocker or verapamil treatment (n=304; 93.8%), combined with disopyramide (n=28; 8.7%); and eligibility for septal reduction therapy (n=96; 29%). At the end of a median follow-up of 66 (34-106) months, 319 (98.2%) were treated for obstruction (n=43 [13.2%] received disopyramide), 46 (14.2%) underwent septal reduction therapy and the all-cause mortality rate was 1.9/100 person-years (95% confidence interval 1.4-2.6) (46 deaths). Moreover, 41 (8.9%) patients from the initial hypertrophic obstructive cardiomyopathy group became eligible for a cardiac myosin inhibitor.
CONCLUSIONS
In this cohort of patients with hypertrophic cardiomyopathy selected from the REMY registry, one third were eligible for a cardiac myosin inhibitor.
Topics: Humans; Male; Cardiomyopathy, Hypertrophic; Female; Middle Aged; Registries; France; Treatment Outcome; Aged; Time Factors; Ventricular Function, Left; Cardiovascular Agents; Patient Selection; Prospective Studies; Cardiac Myosins; Benzylamines; Adult; Risk Factors; Ventricular Outflow Obstruction; Uracil
PubMed: 38762345
DOI: 10.1016/j.acvd.2024.04.001 -
Biomedicine & Pharmacotherapy =... Jun 2024Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are...
Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC.
Topics: Animals; Nitroimidazoles; Female; Disease Models, Animal; Trypanosoma cruzi; Amiodarone; Mice, Inbred C57BL; Drug Therapy, Combination; Chagas Cardiomyopathy; Trypanocidal Agents; Mice; Chagas Disease; Reactive Oxygen Species; Chronic Disease; Parasitemia; Tumor Necrosis Factor-alpha; Parasite Load
PubMed: 38754265
DOI: 10.1016/j.biopha.2024.116742