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Antioxidants & Redox Signaling Aug 2019Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by left ventricular hypertrophy, diastolic dysfunction, and myocardial disarray. Disease... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by left ventricular hypertrophy, diastolic dysfunction, and myocardial disarray. Disease onset occurs between 20 and 50 years of age, thus affecting patients in the prime of their life. HCM is caused by mutations in sarcomere proteins, the contractile building blocks of the heart. Despite increased knowledge of causal mutations, the exact path from genetic defect leading to cardiomyopathy is complex and involves additional disease hits. Laboratory-based studies indicate that HCM development not only depends on the primary sarcomere impairment caused by the mutation but also on secondary disease-related alterations in the heart. Here we propose a vicious mutation-induced disease cycle, in which a mutation-induced energy depletion alters cellular metabolism with increased mitochondrial work, which triggers secondary disease modifiers that will worsen disease and ultimately lead to end-stage HCM. Evidence shows excessive cellular reactive oxygen species (ROS) in HCM patients and HCM animal models. Oxidative stress markers are increased in the heart (oxidized proteins, DNA, and lipids) and serum of HCM patients. In addition, increased mitochondrial ROS production and changes in endogenous antioxidants are reported in HCM. Mutant sarcomeric protein may drive excessive levels of cardiac ROS changes in cardiac efficiency and metabolism, mitochondrial activation and/or dysfunction, impaired protein quality control, and microvascular dysfunction. Interventions restoring metabolism, mitochondrial function, and improved ROS balance may be promising therapeutic approaches. We discuss the effects of current HCM pharmacological therapies and potential future therapies to prevent and reverse HCM. 31, 318-358.
Topics: Alleles; Animals; Calcium; Cardiomyopathy, Hypertrophic; Epigenesis, Genetic; Humans; Mutation; Reactive Oxygen Species; Sarcomeres
PubMed: 29490477
DOI: 10.1089/ars.2017.7236 -
Biological Chemistry Nov 2014The giant sarcomeric protein titin has multiple important functions in striated muscle cells. Due to its gigantic size, its central position in the sarcomere and its... (Review)
Review
The giant sarcomeric protein titin has multiple important functions in striated muscle cells. Due to its gigantic size, its central position in the sarcomere and its elastic I-band domains, titin is a scaffold protein that is important for sarcomere assembly, and serves as a molecular spring that defines myofilament distensibility. This review focuses on the emerging role of titin in mechanosensing and hypertrophic signaling, and further highlights recent evidence that links titin to sarcomeric protein turnover.
Topics: Animals; Connectin; Humans; Mechanotransduction, Cellular; Molecular Chaperones; Protein Conformation; Sarcomeres; Signal Transduction
PubMed: 25205716
DOI: 10.1515/hsz-2014-0178 -
Clinics (Sao Paulo, Brazil) 2013Muscle residual force enhancement has been observed in different muscle preparations for more than half a century. Nonetheless, its mechanism remains unclear; to date,... (Review)
Review
Muscle residual force enhancement has been observed in different muscle preparations for more than half a century. Nonetheless, its mechanism remains unclear; to date, there are three generally accepted hypotheses: 1) sarcomere length non-uniformity, 2) engagement of passive elements, and 3) an increased number of cross-bridges. The first hypothesis uses sarcomere non-homogeneity and instability to explain how "weak" sarcomeres would convey the higher tension generated by an enhanced overlap from "stronger" sarcomeres, allowing the whole system to produce higher forces than predicted by the force-length relationship; non-uniformity provides theoretical support for a large amount of the experimental data. The second hypothesis suggests that passive elements within the sarcomeres (i.e., titin) could gain strain upon calcium activation followed by stretch. Finally, the third hypothesis suggests that muscle stretch after activation would alter cross-bridge kinetics to increase the number of attached cross-bridges. Presently, we cannot completely rule out any of the three hypotheses. Different experimental results suggest that the mechanisms on which these three hypotheses are based could all coexist.
Topics: Biomechanical Phenomena; Humans; Muscle Strength; Organ Size; Sarcomeres
PubMed: 23525326
DOI: 10.6061/clinics/2013(02)r01 -
American Journal of Physiology. Cell... Sep 2018The aim of this study was to determine the role of titin in preventing the development of sarcomere length nonuniformities following activation and after active and...
The aim of this study was to determine the role of titin in preventing the development of sarcomere length nonuniformities following activation and after active and passive stretch by determining the effect of partial titin degradation on sarcomere length nonuniformities and force in passive and active myofibrils. Selective partial titin degradation was performed using a low dose of trypsin. Myofibrils were set at a sarcomere length of 2.4 µm and then passively stretched to sarcomere lengths of 3.4 and 4.4 µm. In the active condition, myofibrils were set at a sarcomere length of 2.8 µm, activated, and actively stretched by 1 µm/sarcomere. The extent of sarcomere length nonuniformities was calculated for each sarcomere as the absolute difference between sarcomere length and the mean sarcomere length of the myofibril. Our main finding is that partial titin degradation does not increase sarcomere length nonuniformities after passive stretch and activation compared with when titin is intact but increases the extent of sarcomere length nonuniformities after active stretch. Furthermore, when titin was partially degraded, active and passive stresses were substantially reduced. These results suggest that titin plays a crucial role in actively stretched myofibrils and is likely involved in active and passive force production.
Topics: Animals; Connectin; Female; Mechanical Phenomena; Muscle Contraction; Muscle Proteins; Myofibrils; Rabbits; Sarcomeres
PubMed: 29768046
DOI: 10.1152/ajpcell.00183.2017 -
Heart, Lung & Circulation Oct 2021Patients with hypertrophic cardiomyopathy (HCM) and an identified sarcomere mutation have worse outcomes than those without though the underlying mechanism is...
BACKGROUND
Patients with hypertrophic cardiomyopathy (HCM) and an identified sarcomere mutation have worse outcomes than those without though the underlying mechanism is incompletely understood. The presence of replacement fibrosis measured by late gadolinium enhancement (LGE) and diffuse fibrosis measured by extracellular volume (ECV) using cardiac magnetic resonance imaging (CMR) are associated with ventricular arrhythmias and cardiac mortality. We aimed to associate these two forms of fibrosis with identified sarcomere mutations.
METHODS AND RESULTS
Three hundred and thirty-six (336) patients with HCM underwent CMR at a single quaternary referral centre between January 2012 and February 2017. Genetic testing was performed in 73 of these patients, yielding an identified sarcomeric mutation in 29 (G+), no mutation in 39 (G-), and a variant of unknown significance (VUS) in five. LGE was more prevalent in G+ compared to G- patients (86 vs. 56%, OR 4.3, p=0.01) and was more extensive (7.5±5.5% of left ventricular [LV] mass vs. 3.0±3.0%, p<0.001). Global ECV from myocardial segments excluding LGE was similar among both groups (26.9±2.9 vs. 25.6±2.8%, p=0.46). However, in G+ patients ECV was greater in the hypertrophied regions of the basal anteroseptum (30.2±7.0 vs. 26.8±3.6%, p=0.004) and basal inferoseptum (28.1±4.3 vs. 26.2±2.9%, p=0.005).
CONCLUSIONS
Genotyped HCM patients with an identified sarcomere mutation have greater LGE and greater regional, but not global, ECV than HCM patients without an identified mutation. This difference in fibrosis may contribute to worse outcomes in patients with an identified HCM mutation.
Topics: Cardiomyopathy, Hypertrophic; Contrast Media; Fibrosis; Gadolinium; Humans; Magnetic Resonance Imaging, Cine; Mutation; Myocardium; Sarcomeres
PubMed: 34023176
DOI: 10.1016/j.hlc.2021.04.008 -
Quarterly Reviews of Biophysics Jan 2023The cardiac sarcomere is a cellular structure in the heart that enables muscle cells to contract. Dozens of proteins belong to the cardiac sarcomere, which work in... (Review)
Review
The cardiac sarcomere is a cellular structure in the heart that enables muscle cells to contract. Dozens of proteins belong to the cardiac sarcomere, which work in tandem to generate force and adapt to demands on cardiac output. Intriguingly, the majority of these proteins have significant intrinsic disorder that contributes to their functions, yet the biophysics of these intrinsically disordered regions (IDRs) have been characterized in limited detail. In this review, we first enumerate these myofilament-associated proteins with intrinsic disorder (MAPIDs) and recent biophysical studies to characterize their IDRs. We secondly summarize the biophysics governing IDR properties and the state-of-the-art in computational tools toward MAPID identification and characterization of their conformation ensembles. We conclude with an overview of future computational approaches toward broadening the understanding of intrinsic disorder in the cardiac sarcomere.
Topics: Myofibrils; Actin Cytoskeleton; Sarcomeres; Computer Simulation; Molecular Conformation
PubMed: 36628457
DOI: 10.1017/S003358352300001X -
The American Journal of Cardiology Feb 2024Genetic testing is an important tool in the diagnosis and management of patients and families with hypertrophic cardiomyopathy (HCM). Modern testing can identify...
Genetic testing is an important tool in the diagnosis and management of patients and families with hypertrophic cardiomyopathy (HCM). Modern testing can identify causative variants in 30 to >60% of patients, with probability of a positive test varying with baseline characteristics such as known family history of HCM. Patients diagnosed with HCM should be offered genetic counseling and genetic testing as appropriate. Standard multigene panels evaluate sarcomeric genes known to cause HCM as well as genetic conditions that can mimic HCM but require different management. Positive genetic testing (finding a pathogenic or likely pathogenic variant) helps to clarify diagnosis and assists in family screening. If there is high confidence that an identified variant is the cause of HCM, at-risk family members can pursue predictive testing to determine if they are truly at risk or if they can be dismissed from serial screening based on whether they inherited the family's causative variant. Interpreting test results can be complex, and providers should make use of multidisciplinary teams as well as evidence-based resources to obtain the best possible understanding of pathogenicity.
Topics: Humans; Genetic Testing; Cardiomyopathy, Hypertrophic; Genetic Counseling; Family; Sarcomeres; Mutation
PubMed: 38368035
DOI: 10.1016/j.amjcard.2023.10.032 -
Progress in Biophysics and Molecular... 2003Measurements of the geometry and fibrous-sheet structure of the left and right ventricles of the pig heart are fitted with a finite element model. Mechanical changes... (Review)
Review
Measurements of the geometry and fibrous-sheet structure of the left and right ventricles of the pig heart are fitted with a finite element model. Mechanical changes during the heart cycle are computed by solving the equations of motion under specified ventricular boundary conditions and using experimentally defined constitutive laws for the active and passive material properties of myocardial tissue. The resulting patterns of deformation, such as axial torsion and changes in wall thickness and base-apex length, are consistent with experimental observations. The model can therefore be used to predict sarcomere length changes and other strain patterns throughout the myocardium and throughout the cardiac cycle. Here we present sarcomere length changes at a limited number of material points within the wall. Sarcomere length typically varies by 10% above and below the unloaded length; although under the boundary conditions imposed in the current model the midwall circumferentially oriented sarcomere lengths increased by up to 20% at end diastole. We provide web-access details for a downloadable software program designed to provide more extensive information on mechanical deformation, such as the principal strains and muscle fibre cross-sectional area changes during the cardiac cycle.
Topics: Animals; Endocardium; Heart Ventricles; Models, Anatomic; Models, Cardiovascular; Models, Theoretical; Myocardial Contraction; Myocardium; Sarcomeres; Software; Swine; Time Factors; Ventricular Function; Ventricular Function, Left
PubMed: 12732282
DOI: 10.1016/s0079-6107(03)00023-3 -
Journal of Applied Physiology... Oct 1999Relaxation is the process by which, after contraction, the muscle actively returns to its initial conditions of length and load. In rhythmically active muscles such as... (Review)
Review
Relaxation is the process by which, after contraction, the muscle actively returns to its initial conditions of length and load. In rhythmically active muscles such as diaphragm, relaxation is of physiological importance because diaphragm must return to a relatively constant resting position at the end of each contraction-relaxation cycle. Rapid and complete relaxation of the diaphragm is likely to play an important role in adaptation to changes in respiratory load and breathing frequency. Regulation of diaphragm relaxation at the molecular and cellular levels involves Ca(2+) removal from the myofilaments, active Ca(2+) pumping by the sarcoplasmic reticulum (SR), and decrease in the number of working cross bridges. The relative contribution of these mechanisms mainly depends on sarcomere length, muscle tension, and the intrinsic contractile function. Increased capacity of SR to take up Ca(2+) can arise from increased density of active SR pumping sites or in slow-twitch fibers from phosphorylation of phospholamban, whereas impaired coupling between ATP hydrolysis and Ca(2+) transport into the SR or intracellular acidosis reduces SR Ca(2+) pump activity. In experimental conditions of decreased contractile performance, slowed, enhanced, or unchanged relaxation rates have been reported in vitro. In vivo, a slowing in the rate of decline of the respiratory pressure is generally considered an early reliable index of respiratory muscle fatigue. Impaired relaxation rate may, in turn, favor mismatch between blood flow and metabolic demand, especially at high breathing frequencies.
Topics: Animals; Diaphragm; Humans; Isometric Contraction; Muscle Relaxation; Respiratory Physiological Phenomena; Sarcomeres
PubMed: 10517748
DOI: 10.1152/jappl.1999.87.4.1243 -
The Journal of Physiology Aug 2022The force-pCa (F-pCa) curve is used to characterize steady-state contractile properties of cardiac muscle cells in different physiological, pathological and...
The force-pCa (F-pCa) curve is used to characterize steady-state contractile properties of cardiac muscle cells in different physiological, pathological and pharmacological conditions. This provides a reduced preparation in which to isolate sarcomere mechanisms. However, it is unclear how changes in the F-pCa curve impact emergent whole-heart mechanics quantitatively. We study the link between sarcomere and whole-heart function using a multiscale mathematical model of rat biventricular mechanics that describes sarcomere, tissue, anatomy, preload and afterload properties quantitatively. We first map individual cell-level changes in sarcomere-regulating parameters to organ-level changes in the left ventricular function described by pressure-volume loop characteristics (e.g. end-diastolic and end-systolic volumes, ejection fraction and isovolumetric relaxation time). We next map changes in the sarcomere-regulating parameters to changes in the F-pCa curve. We demonstrate that a change in the F-pCa curve can be caused by multiple different changes in sarcomere properties. We demonstrate that changes in sarcomere properties cause non-linear and, importantly, non-monotonic changes in left ventricular function. As a result, a change in sarcomere properties yielding changes in the F-pCa curve that improve contractility does not guarantee an improvement in whole-heart function. Likewise, a desired change in whole-heart function (i.e. ejection fraction or relaxation time) is not caused by a unique shift in the F-pCa curve. Changes in the F-pCa curve alone cannot be used to predict the impact of a compound on whole-heart function. KEY POINTS: The force-pCa (F-pCa) curve is used to assess myofilament calcium sensitivity after pharmacological modulation and to infer pharmacological effects on whole-heart function. We demonstrate that there is a non-unique mapping from changes in F-pCa curves to changes in left ventricular (LV) function. The effect of changes in F-pCa on LV function depend on the state of the heart and could be different for different pathological conditions. Screening of compounds to impact whole-heart function by F-pCa should be combined with active tension and calcium transient measurements to predict better how changes in muscle function will impact whole-heart physiology.
Topics: Animals; Calcium; Myocardial Contraction; Myocytes, Cardiac; Myofibrils; Rats; Sarcomeres
PubMed: 35737959
DOI: 10.1113/JP283352