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International Journal of Molecular... Aug 2021Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 people in the general population. Although characterized by... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 people in the general population. Although characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray, and cardiac fibrosis, HCM is in fact a highly complex disease with heterogenous clinical presentation, onset, and complications. While HCM is generally accepted as a disease of the sarcomere, variable penetrance in families with identical genetic mutations challenges the monogenic origin of HCM and instead implies a multifactorial cause. Furthermore, large-scale genome sequencing studies revealed that many genes previously reported as causative of HCM in fact have little or no evidence of disease association. These findings thus call for a re-evaluation of the sarcomere-centered view of HCM pathogenesis. Here, we summarize our current understanding of sarcomere-independent mechanisms of cardiomyocyte hypertrophy, highlight the role of extracellular signals in cardiac fibrosis, and propose an alternative but integrated model of HCM pathogenesis.
Topics: Cardiomyopathy, Hypertrophic; Genetic Predisposition to Disease; Humans; Phenotype; Sarcomeres
PubMed: 34445638
DOI: 10.3390/ijms22168933 -
Journal of Molecular and Cellular... Feb 2019Cardiac mechanics plays a crucial role in atrial and ventricular function, in the regulation of growth and remodelling, in the progression of disease, and the response... (Review)
Review
Cardiac mechanics plays a crucial role in atrial and ventricular function, in the regulation of growth and remodelling, in the progression of disease, and the response to treatment. The spatial scale of the critical mechanisms ranges from nm (molecules) to cm (hearts) with the fastest events occurring in milliseconds (molecular events) and the slowest requiring months (growth and remodelling). Due to its complexity and importance, cardiac mechanics has been studied extensively both experimentally and through mathematical models and simulation. Models of cardiac mechanics evolved from seminal studies in skeletal muscle, and developed into cardiac specific, species specific, human specific and finally patient specific calculations. These models provide a formal framework to link multiple experimental assays recorded over nearly 100 years into a single unified representation of cardiac function. This review first provides a summary of the proteins, physiology and anatomy involved in the generation of cardiac pump function. We then describe the evolution of models of cardiac mechanics starting with the early theoretical frameworks describing the link between sarcomeres and muscle contraction, transitioning through myosin-level models to calcium-driven systems, and ending with whole heart patient-specific models.
Topics: Actin Cytoskeleton; Animals; Biomechanical Phenomena; Heart; Humans; Models, Biological; Myocardial Contraction; Sarcomeres
PubMed: 30503754
DOI: 10.1016/j.yjmcc.2018.11.015 -
Journal of Molecular and Cellular... Jan 2019Morphology underlies subdivision of the primary/heritable sarcomeric cardiomyopathies (CMs) into hypertrophic (HCM) and dilated (DCM). Next-generation DNA-sequencing... (Review)
Review
Morphology underlies subdivision of the primary/heritable sarcomeric cardiomyopathies (CMs) into hypertrophic (HCM) and dilated (DCM). Next-generation DNA-sequencing (NGS) has identified important disease-variants, improving CM diagnosis, management, genetic screening, and prognosis. Although monogenic (Mendelian) analyses directly point at downstream studies, they disregard coexisting genomic variations and gene-by-gene interactions molding detailed CM-phenotypes. In-place of polygenic models, in accounting for observed defective genotype-phenotype correlations, fuzzy concepts having gradations of significance and unsharp domain-boundaries are invoked, including pleiotropy, genetic-heterogeneity, incomplete penetrance, and variable expressivity. HCM and DCM undoubtedly entail cooperativity of unidentified/elusive causative genomic-variants. Modern genomics can exploit comprehensive electronic/digital health records, facilitating consideration of multifactorial variant-models. Genome-wide association studies entailing high-fidelity solid-state catheterization, multimodal-imaging, molecular cardiology, systems biology and bioinformatics, will decipher accurate genotype-phenotype correlations and identify novel therapeutic-targets, fostering personalized medicine/cardiology. This review surveys successes and challenges of genetic/genomic approaches to CMs, and their impact on current and future clinical care.
Topics: Biological Variation, Population; Biomechanical Phenomena; Cardiomyopathies; Humans; Multifactorial Inheritance; Sarcomeres; Translational Research, Biomedical
PubMed: 30423317
DOI: 10.1016/j.yjmcc.2018.10.024 -
Journal of the American College of... Apr 2019Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. However, limitations of this... (Review)
Review
Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. However, limitations of this hypothesis suggest that sarcomere mutations alone do not adequately explain all HCM clinical and pathobiological features. Disease-causing sarcomere mutations are absent in ∼70% of patients with established disease, and sarcomere gene carriers can live to advanced ages without developing HCM. Some features of HCM are also inconsistent with the single sarcomere gene hypothesis, such as regional left ventricular hypertrophy and myocardial fibrosis, as well as structurally abnormal elongated mitral valve leaflets and remodeled intramural coronary arterioles, which involve tissue types that do not express cardiomyocyte sarcomere proteins. It is timely to expand the HCM research focus beyond a single molecular event toward more inclusive models to explain this disease in its entirety. The authors chart paths forward addressing this knowledge gap using novel analytical approaches, particularly network medicine, to unravel the pathobiological complexity of HCM.
Topics: Cardiomyopathy, Hypertrophic; Female; Genetic Heterogeneity; Genetic Predisposition to Disease; Humans; Male; Mutation; Prevalence; Prognosis; Risk Assessment; Sarcomeres; Survival Analysis
PubMed: 31000001
DOI: 10.1016/j.jacc.2019.01.061 -
Physiological Reports Mar 2021The force-length relation of the skeletal muscles is an important factor influencing the joint torque at a given joint angle. We aimed to clarify the relationship...
The force-length relation of the skeletal muscles is an important factor influencing the joint torque at a given joint angle. We aimed to clarify the relationship between the resting sarcomere length and knee joint angle in the vastus intermedius (VI) and to compare it with that of the vastus lateralis (VL). The left and right legs were fixed at knee joint angles of 0° and 90°, respectively, in seven cadavers (age at the time of death: 70-91 years). Muscle tissues were dissected by necropsy of the VL and the VI, and electron microscopy images were obtained to calculate the sarcomere length. At knee joint angles of 0° and 90°, the VL sarcomere length was 2.28 ± 0.49 μm and 2.30 ± 0.48 μm, respectively, and the VI sarcomere length was 2.19 ± 0.35 μm and 2.46 ± 0.53 μm, respectively, with a significant difference between the two (p = 0.028). The magnitude of sarcomere length changes with knee joint angle changes was significantly greater for the VI (0.27 ± 0.20 μm) than for the VL (0.02 ± 0.09 μm) (p = 0.009). Thus, knee joint angle changes may affect the passive and active tension produced by the VI more than those produced by the VL.
Topics: Biomechanical Phenomena; Cadaver; Humans; Knee Joint; Muscle Contraction; Muscle, Skeletal; Quadriceps Muscle; Range of Motion, Articular; Sarcomeres
PubMed: 33650805
DOI: 10.14814/phy2.14771 -
Developmental Dynamics : An Official... Jan 2021Muscle myofibrils and sarcomeres present exceptional examples of highly ordered cytoskeletal filament arrays, whose distinct spatial organization is an essential aspect...
BACKGROUND
Muscle myofibrils and sarcomeres present exceptional examples of highly ordered cytoskeletal filament arrays, whose distinct spatial organization is an essential aspect of muscle cell functionality. We utilized ultra-structural analysis to investigate the assembly of myofibrils and sarcomeres within developing myotubes of the indirect flight musculature of Drosophila.
RESULTS
A temporal sequence composed of three major processes was identified: subdivision of the unorganized cytoplasm of nascent, multi-nucleated myotubes into distinct organelle-rich and filament-rich domains; initial organization of the filament-rich domains into myofibrils harboring nascent sarcomeric units; and finally, maturation of the highly-ordered pattern of sarcomeric thick (myosin-based) and thin (microfilament-based) filament arrays in parallel to myofibril radial growth. Significantly, organized microtubule arrays were present throughout these stages and exhibited dynamic changes in their spatial patterns consistent with instructive roles. Genetic manipulations confirm these notions, and imply specific and critical guidance activities of the microtubule-based cytoskeleton, as well as structural interdependence between the myosin- and actin-based filament arrays.
CONCLUSIONS
Our observations highlight a surprisingly significant, behind-the-scenes role for microtubules in establishment of myofibril and sarcomere spatial patterns and size, and provide a detailed account of the interplay between major cytoskeletal elements in generating these essential contractile myogenic units.
Topics: Animals; Cytoskeleton; Drosophila; Muscle Development; Pupa; Sarcomeres
PubMed: 32725855
DOI: 10.1002/dvdy.227 -
Journal of the American Heart... Dec 2023Mutations to the co-chaperone protein BAG3 (B-cell lymphoma-2-associated athanogene-3) are a leading cause of dilated cardiomyopathy (DCM). These mutations often impact...
BACKGROUND
Mutations to the co-chaperone protein BAG3 (B-cell lymphoma-2-associated athanogene-3) are a leading cause of dilated cardiomyopathy (DCM). These mutations often impact the C-terminal BAG domain (residues 420-499), which regulates heat shock protein 70-dependent protein turnover via autophagy. While mutations in other regions are less common, previous studies in patients with DCM found that co-occurrence of 2 variants (P63A, P380S) led to worse prognosis. However, the underlying mechanism for dysfunction is not fully understood.
METHODS AND RESULTS
In this study, we used proteomics, Western blots, and myofilament functional assays on left ventricular tissue from patients with nonfailing, DCM, and DCM with to determine how these mutations impact protein quality control and cardiomyocyte contractile function. We found dysregulated autophagy and increased protein ubiquitination in patients with compared with nonfailing and DCM, suggesting impaired protein turnover. Expression and myofilament localization of BAG3-binding proteins were also uniquely altered in the including abolished localization of the small heat shock protein CRYAB (alpha-crystallin B chain) to the sarcomere. To determine whether these variants impacted sarcomere function, we used cardiomyocyte force-calcium assays and found reduced maximal calcium-activated force in DCM and . Interestingly, myofilament calcium sensitivity was increased in DCM but not with , which was not explained by differences in troponin I phosphorylation.
CONCLUSIONS
Together, our data support that the disease-enhancing mechanism for variants outside of the BAG domain is through disrupted protein turnover leading to compromised sarcomere function. These findings suggest a shared mechanism of disease among pathogenic variants, regardless of location.
Topics: Humans; Sarcomeres; Calcium; Apoptosis Regulatory Proteins; Cardiomyopathy, Dilated; Heart Failure; Autophagy; Adaptor Proteins, Signal Transducing
PubMed: 38108245
DOI: 10.1161/JAHA.123.029938 -
The Indian Journal of Medical Research Aug 2023Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease that frequently causes sudden cardiac death (SCD) among young adults. Several pathogenic mutations in... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease that frequently causes sudden cardiac death (SCD) among young adults. Several pathogenic mutations in genes encoding the cardiac sarcomere have been identified as diagnostic factors for HCM and proposed as prognostic markers for SCD. The objective of this review was to determine the scope of available literature on the variants encoding sarcomere proteins associated with SCD reported among Indian patients with HCM. The eligibility criteria for the scoping review included full text articles that reported the results of genetic screening for sarcomeric gene mutations in HCM patients of Indian south Asian ancestry. We systematically reviewed studies from the databases of Medline, Scopus, Web of Science core collection and Google Scholar. The electronic search strategy included a combination of generic terms related to genetics, disease and population. The protocol of the study was registered with Open Science Framework (https://osf.io/53gde/). A total of 19 articles were identified that reported pathogenic or likely pathogenic (P/LP) variants within MYH7, MYBPC3, TNNT2, TNNI3 and TPM1 genes, that included 16 singletons, one de novo and one digenic mutation (MYH7/ TPM1) associated with SCD among Indian patients. Evidence from functional studies and familial segregation implied a plausible mechanistic role of these P/LP variants in HCM pathology. This scoping review has compiled all the P/LP variants reported to-date among Indian patients and summarized their association with SCD. Single homozygous, de novo and digenic mutations were observed to be associated with severe phenotypes compared to single heterozygous mutations. The abstracted genetic information was updated with reference sequence ID (rsIDs) and compiled into freely accessible HCMvar database, available at https://hcmvar.heartfailure.org.in/. This can be used as a population specific genetic database for reference by clinicians and researchers involved in the identification of diagnostic and prognostic markers for HCM.
Topics: Humans; Young Adult; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Heart; Mutation; Sarcomeres
PubMed: 37787257
DOI: 10.4103/ijmr.ijmr_3567_21 -
Trends in Molecular Medicine Sep 2019Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular disease where cardiac dysfunction often associates with mutations in sarcomeric genes.... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular disease where cardiac dysfunction often associates with mutations in sarcomeric genes. Various models based on tissue explants, isolated cardiomyocytes, skinned myofibrils, and purified actin/myosin preparations have uncovered disease hallmarks, enabling the development of putative therapeutics, with some reaching clinical trials. Newly developed human pluripotent stem cell (hPSC)-based models could be complementary by overcoming some of the inconsistencies of earlier systems, whilst challenging and/or clarifying previous findings. In this article we compare recent progress in unveiling multiple HCM mechanisms in different models, highlighting similarities and discrepancies. We explore how insight is facilitating the design of new HCM therapeutics, including those that regulate metabolism, contraction and heart rhythm, providing a future perspective for treatment of HCM.
Topics: Animals; Biomarkers; CRISPR-Cas Systems; Cardiomyopathy, Hypertrophic; Disease Models, Animal; Disease Susceptibility; Gene Editing; Humans; Models, Biological; Molecular Targeted Therapy; Muscle Contraction; Myocardium; Myocytes, Cardiac; Pluripotent Stem Cells; Sarcomeres
PubMed: 31324451
DOI: 10.1016/j.molmed.2019.06.005 -
International Journal of Molecular... Apr 2020Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding... (Review)
Review
Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.
Topics: Animals; Carrier Proteins; Filamins; Humans; Models, Molecular; Molecular Structure; Muscle Cells; Muscular Diseases; Mutation; Protein Binding; Protein Conformation; Protein Processing, Post-Translational; Sarcomeres; Structure-Activity Relationship
PubMed: 32295012
DOI: 10.3390/ijms21082696