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International Journal of Molecular... Apr 2024Mutations in the gene-encoding A-type lamins can cause Limb-Girdle muscular dystrophy Type 1B (LGMD1B). This disease presents with weakness and wasting of the proximal...
Mutations in the gene-encoding A-type lamins can cause Limb-Girdle muscular dystrophy Type 1B (LGMD1B). This disease presents with weakness and wasting of the proximal skeletal muscles and has a variable age of onset and disease severity. This variability has been attributed to genetic background differences among individuals; however, such variants have not been well characterized. To identify such variants, we investigated a multigeneration family in which affected individuals are diagnosed with LGMD1B. The primary genetic cause of LGMD1B in this family is a dominant mutation that activates a cryptic splice site, leading to a five-nucleotide deletion in the mature mRNA. This results in a frame shift and a premature stop in translation. Skeletal muscle biopsies from the family members showed dystrophic features of variable severity, with the muscle fibers of some family members possessing cores, regions of sarcomeric disruption, and a paucity of mitochondria, not commonly associated with LGMD1B. Using whole genome sequencing (WGS), we identified 21 DNA sequence variants that segregate with the family members possessing more profound dystrophic features and muscle cores. These include a relatively common variant in (). This variant was given priority because another mutation in causes autosomal dominant centronuclear myopathy-4, which causes cores in addition to centrally positioned nuclei. Therefore, we analyzed muscle biopsies from family members and discovered that those with both the mutation and the variant contain muscle cores that accumulated both CCDC78 and RyR1. Muscle cores containing mislocalized CCDC78 and RyR1 were absent in the less profoundly affected family members possessing only the mutation. Taken together, our findings suggest that a relatively common variant in can impart profound muscle pathology in combination with a mutation and accounts for variability in skeletal muscle disease phenotypes.
Topics: Adult; Female; Humans; Male; Middle Aged; Lamin Type A; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Mutation; Pedigree; Microtubule-Associated Proteins
PubMed: 38732148
DOI: 10.3390/ijms25094930 -
Journal of Medicinal Chemistry May 2024Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of...
Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound , a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator . Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.
Topics: Humans; Animals; Myocardial Contraction; Cardiovascular Diseases; Rats; Structure-Activity Relationship; Male; Drug Discovery; Troponin; Mice; Rats, Sprague-Dawley; Sulfonamides
PubMed: 38729623
DOI: 10.1021/acs.jmedchem.3c02413 -
Journal of Biomechanics May 2024Connective tissues can be recognized as an important structural support element in muscles. Recent studies have also highlighted its importance in active force...
Connective tissues can be recognized as an important structural support element in muscles. Recent studies have also highlighted its importance in active force generation and transmission between muscles, particularly through the epimysium. In the present study, we aimed to investigate the impact of the endomysium, the connective tissue surrounding muscle fibers, on both passive and active force production. Pairs of skeletal muscle fibers were extracted from the extensor digitorum longus muscles of rats and, after chemical skinning, their passive and active force-length relationships were measured under two conditions: (i) with the endomysium between muscle fibers intact, and (ii) after its dissection. We found that the dissection of the endomysium caused force to significantly decrease in both active (by 22.2 % when normalized to the maximum isometric force; p < 0.001) and passive conditions (by 25.9 % when normalized to the maximum isometric force; p = 0.034). These findings indicate that the absence of endomysium compromises muscle fiber's not only passive but also active force production. This effect may be attributed to increased heterogeneity in sarcomere lengths, enhanced lattice spacing between myofilaments, or a diminished role of trans-sarcolemmal proteins due to dissecting the endomysium. Future investigations into the underlying mechanisms and their implications for various extracellular matrix-related diseases are warranted.
Topics: Animals; Rats; Muscle Fibers, Skeletal; Rats, Wistar; Connective Tissue; Sarcomeres; Male; Muscle, Skeletal; Biomechanical Phenomena; Isometric Contraction; Muscle Contraction
PubMed: 38723428
DOI: 10.1016/j.jbiomech.2024.112134 -
Circulation Jun 2024The "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy" provides recommendations to guide clinicians in the management of...
2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.
AIM
The "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy" provides recommendations to guide clinicians in the management of patients with hypertrophic cardiomyopathy.
METHODS
A comprehensive literature search was conducted from September 14, 2022, to November 22, 2022, encompassing studies, reviews, and other evidence on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through May 23, 2023, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate.
STRUCTURE
Hypertrophic cardiomyopathy remains a common genetic heart disease reported in populations globally. Recommendations from the "2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy" have been updated with new evidence to guide clinicians.
Topics: Humans; American Heart Association; Cardiology; Cardiomyopathy, Hypertrophic; Disease Management; United States
PubMed: 38718139
DOI: 10.1161/CIR.0000000000001250 -
Cardiovascular Diagnosis and Therapy Apr 2024Sarcomeric hypertrophic cardiomyopathy (HCM) must be differentiated from phenotypically similar conditions because clinical management and prognosis may greatly differ....
BACKGROUND
Sarcomeric hypertrophic cardiomyopathy (HCM) must be differentiated from phenotypically similar conditions because clinical management and prognosis may greatly differ. Patients with unexplained left ventricular hypertrophy require an early, confirmed genetic diagnosis through diagnostic or predictive genetic testing. We tested the feasibility and practicality of the application of a 17-gene next-generation sequencing (NGS) panel to detect the most common genetic causes of HCM and HCM phenocopies, including treatable phenocopies, and report detection rates. Identification of transthyretin cardiac amyloidosis (ATTR-CA) and Fabry disease (FD) is essential because of the availability of disease-specific therapy. Early initiation of these treatments may lead to better clinical outcomes.
METHODS
In this international, multicenter, cross-sectional pilot study, peripheral dried blood spot samples from patients of cardiology clinics with an unexplained increased left ventricular wall thickness (LVWT) of ≥13 mm in one or more left ventricular myocardial segments (measured by imaging methods) were analyzed at a central laboratory. NGS included the detection of known splice regions and flanking regions of 17 genes using the Illumina NextSeq 500 and NovaSeq 6000 sequencing systems.
RESULTS
Samples for NGS screening were collected between May 2019 and October 2020 at cardiology clinics in Colombia, Brazil, Mexico, Turkey, Israel, and Saudi Arabia. Out of 535 samples, 128 (23.9%) samples tested positive for pathogenic/likely pathogenic genetic variants associated with HCM or HCM phenocopies with double pathogenic/likely pathogenic variants detected in four samples. Among the 132 (24.7%) detected variants, 115 (21.5%) variants were associated with HCM and 17 (3.2%) variants with HCM phenocopies. Variants in (n=60, 11.2%) and (n=41, 7.7%) were the most common HCM variants. The HCM phenocopy variants included variants in the (n=7, 1.3%) and (n=2, 0.4%) genes. The mean (standard deviation) ages of patients with HCM or HCM phenocopy variants, including and variants, were 42.8 (17.9), 54.6 (17.0), and 69.0 (1.4) years, respectively.
CONCLUSIONS
The overall diagnostic yield of 24.7% indicates that the screening strategy effectively identified the most common forms of HCM and HCM phenocopies among geographically dispersed patients. The results underscore the importance of including ATTR-CA ( variants) and FD ( variants), which are treatable disorders, in the differential diagnosis of patients with increased LVWT of unknown etiology.
PubMed: 38716318
DOI: 10.21037/cdt-23-191 -
Veterinary and Animal Science Jun 2024This study compared the effect of four levels of K Humate S100R (potassium humate) supplementation on the quality, shelf-life, and nutritional properties of beef. Angus...
This study compared the effect of four levels of K Humate S100R (potassium humate) supplementation on the quality, shelf-life, and nutritional properties of beef. Angus steers ( = 40) were individually housed and fed either 0, 35, 70, or 140 g K Humate S100R/animal/day for 100 days, following a 30 day adjustment period. The steers were slaughtered at the completion of the feeding study. The left m. (LL) was collected at 24 h and aged for either 2 or 6 weeks before analysis. K Humate S100R supplementation did not affect beef drip loss, cooking loss, shear force, sarcomere length, ultimate pH, intramuscular fat content, or total volatile basic nitrogen concentrations ( > 0.05). Steers supplemented with 70 g/day K Humate S100R produced beef with higher * values on Days 1 and 3 of retail display ( < 0.05). Beef mineral composition was unchanged by K Humate S100R supplementation ( > 0.05), but there were minor changes to the fatty acid profile. Specifically, the ratio of omega-6 to omega-3 ( < 0.05) and C20:2n-6 concentrations ( < 0.05) increased with supplementation level. Together, these results demonstrate no detrimental effects on beef quality and shelf-life as a result of K Humate S100R supplementation.
PubMed: 38706515
DOI: 10.1016/j.vas.2024.100355 -
Clinics (Sao Paulo, Brazil) 2024The purpose of this study is to develop an animal model of Chronic Intermittent Hypoxia (CIH) and investigate the role of the TRPC5 channel in cardiac damage in OSAHS...
OBJECTIVE
The purpose of this study is to develop an animal model of Chronic Intermittent Hypoxia (CIH) and investigate the role of the TRPC5 channel in cardiac damage in OSAHS rats.
METHODS
Twelve male Sprague Dawley rats were randomly divided into the CIH group and the Normoxic Control (NC) group. Changes in structure, function, and pathology of heart tissue were observed through echocardiography, transmission electron microscopy, HE-staining, and TUNEL staining.
RESULTS
The Interventricular Septum thickness at diastole (IVSd) and End-Diastolic Volume (EDV) of rats in the CIH group significantly increased, whereas the LV ejection fraction and LV fraction shortening significantly decreased. TEM showed that the myofilaments in the CIH group were loosely arranged, the sarcomere length varied, the cell matrix dissolved, the mitochondrial cristae were partly flocculent, the mitochondrial outer membrane dissolved and disappeared, and some mitochondria were swollen and vacuolated. The histopathological examination showed that the cardiomyocytes in the CIH group were swollen with granular degeneration, some of the myocardial fibers were broken and disorganized, and most of the nuclei were vacuolar and hypochromic.
CONCLUSION
CIH promoted oxidative stress, the influx of Ca, and the activation of the CaN/NFATc signaling pathway, which led to pathological changes in the morphology and ultrastructure of cardiomyocytes, the increase of myocardial apoptosis, and the decrease of myocardial contractility. These changes may be associated with the upregulation of TRPC5.
Topics: Animals; Male; Rats; Apoptosis; Chronic Disease; Disease Models, Animal; Echocardiography; Hypoxia; In Situ Nick-End Labeling; Microscopy, Electron, Transmission; Myocardium; Myocytes, Cardiac; Oxidative Stress; Random Allocation; Rats, Sprague-Dawley; TRPC Cation Channels
PubMed: 38703717
DOI: 10.1016/j.clinsp.2024.100368 -
Medicine May 2024Familial hypertrophic cardiomyopathy (FHCM) is an inherited cardiac disease caused by mutations of sarcomere proteins and can be the underlining substrate for major... (Review)
Review
Familial hypertrophic cardiomyopathy (FHCM) is an inherited cardiac disease caused by mutations of sarcomere proteins and can be the underlining substrate for major cardiovascular events. Early identification and diagnosis of FHCM are essential to reduce sudden cardiac death. So, this paper summarized the current knowledge on FHCM, and displayed the analysis via bibliometrics method. The relevant literature on FHCM were screened searched via the Web of Science Core Collection database from 2012 to 2022. The literatures were was summarized and analyzed via the bibliometrics method analyzed via CiteSpace and VOSviewer according to topic categories, distribution of spatiotemporal omics and authors, as well as references. Since 2012, there are 909 research articles and reviews related to FHCM. The number of publication for the past 10 years have shown that the development of FHCM research has been steady, with the largest amount of literature in 2012. The most published papers were from the United States, followed by the United Kingdom and Italy. The University of London (63 papers) was the institution that published the most research articles, followed by Harvard University (45 papers) and University College London (45 papers). Keywords formed 3 clusters, focused on the pathogenesis of FHCM, the diagnosis of FHCM, FHCM complications, respectively. The bibliometric analysis and visualization techniques employed herein highlight key trends and focal points in the field, predominantly centered around FHCM's pathogenesis, diagnostic approaches, and its complications. These insights are instrumental in steering future research directions in this area.
Topics: Bibliometrics; Humans; Cardiomyopathy, Hypertrophic, Familial; Biomedical Research
PubMed: 38701258
DOI: 10.1097/MD.0000000000037969 -
PloS One 2024Myogenesis is regulated mainly by transcription factors known as Myogenic Regulatory Factors (MRFs), and the transcription is affected by epigenetic modifications....
Myogenesis is regulated mainly by transcription factors known as Myogenic Regulatory Factors (MRFs), and the transcription is affected by epigenetic modifications. However, the epigenetic regulation of myogenesis is poorly understood. Here, we focused on the epigenomic modification enzyme, PHF2, which demethylates histone 3 lysine 9 dimethyl (H3K9me2) during myogenesis. Phf2 mRNA was expressed during myogenesis, and PHF2 was localized in the nuclei of myoblasts and myotubes. We generated Phf2 knockout C2C12 myoblasts using the CRISPR/Cas9 system and analyzed global transcriptional changes via RNA-sequencing. Phf2 knockout (KO) cells 2 d post differentiation were subjected to RNA sequencing. Gene ontology (GO) analysis revealed that Phf2 KO impaired the expression of the genes related to skeletal muscle fiber formation and muscle cell development. The expression levels of sarcomeric genes such as Myhs and Mybpc2 were severely reduced in Phf2 KO cells at 7 d post differentiation, and H3K9me2 modification of Mybpc2, Mef2c and Myh7 was increased in Phf2 KO cells at 4 d post differentiation. These findings suggest that PHF2 regulates sarcomeric gene expression via epigenetic modification.
Topics: Animals; Mice; Cell Differentiation; Cell Line; Epigenesis, Genetic; Gene Knockout Techniques; Histone Demethylases; Histones; MEF2 Transcription Factors; Muscle Development; Muscle Fibers, Skeletal; Myoblasts; Myosin Heavy Chains; Sarcomeres; Transcription Factors; Transcription, Genetic
PubMed: 38701072
DOI: 10.1371/journal.pone.0301690 -
APL Bioengineering Jun 2024Cardiac tissue engineering has emerged as a promising approach for restoring the functionality of damaged cardiac tissues following myocardial infarction. To effectively...
Cardiac tissue engineering has emerged as a promising approach for restoring the functionality of damaged cardiac tissues following myocardial infarction. To effectively replicate the native anisotropic structure of cardiac tissues , this study focused on the fabrication of micropatterned gelatin methacryloyl hydrogels with varying geometric parameters. These substrates were evaluated for their ability to guide induced pluripotent stem cell-derived cardiomyocytes (CMs). The findings demonstrate that the mechanical properties of this hydrogel closely resemble those of native cardiac tissues, and it exhibits high fidelity in micropattern fabrication. Micropatterned hydrogel substrates lead to enhanced organization, maturation, and contraction of CMs. A microgroove with 20-m-width and 20-m-spacing was identified as the optimal configuration for maximizing the contact guidance effect, supported by analyses of nuclear orientation and F-actin organization. Furthermore, this specific micropattern design was found to promote CMs' maturation, as evidenced by increased expression of connexin 43 and vinculin, along with extended sarcomere length. It also enhanced CMs' contraction, resulting in larger contractile amplitudes and greater contractile motion anisotropy. In conclusion, these results underscore the significant benefits of optimizing micropatterned gelatin methacryloyl for improving CMs' organization, maturation, and contraction. This valuable insight paves the way for the development of highly organized and functionally mature cardiac tissues .
PubMed: 38699629
DOI: 10.1063/5.0182585