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Cardiovascular Research Apr 2015The clinical variability in patients with sarcomeric cardiomyopathies is striking: a mutation causes cardiomyopathy in one individual, while the identical mutation is... (Review)
Review
The clinical variability in patients with sarcomeric cardiomyopathies is striking: a mutation causes cardiomyopathy in one individual, while the identical mutation is harmless in a family member. Moreover, the clinical phenotype varies ranging from asymmetric hypertrophy to severe dilatation of the heart. Identification of a single phenotype-associated disease mechanism would facilitate the design of targeted treatments for patient groups with different clinical phenotypes. However, evidence from both the clinic and basic knowledge of functional and structural properties of the sarcomere argues against a 'one size fits all' therapy for treatment of one clinical phenotype. Meticulous clinical and basic studies are needed to unravel the initial and progressive changes initiated by sarcomere mutations to better understand why mutations in the same gene can lead to such opposing phenotypes. Ultimately, we need to design an 'integrative physiology' approach to fully realize patient/gene-tailored therapy. Expertise within different research fields (cardiology, genetics, cellular biology, physiology, and pharmacology) must be joined to link longitudinal clinical studies with mechanistic insights obtained from molecular and functional studies in novel cardiac muscle systems. New animal models, which reflect both initial and more advanced stages of sarcomeric cardiomyopathy, will also aid in achieving these goals. Here, we discuss current priorities in clinical and preclinical investigation aimed at increasing our understanding of pathophysiological mechanisms leading from mutation to disease. Such information will provide the basis to improve risk stratification and to develop therapies to prevent/rescue cardiac dysfunction and remodelling caused by sarcomere mutations.
Topics: Animals; Biomedical Research; Cardiology; Cardiomyopathies; Genetic Markers; Genetic Predisposition to Disease; Humans; Mutation; Phenotype; Research; Sarcomeres
PubMed: 25631582
DOI: 10.1093/cvr/cvv019 -
Journal of Biomechanics Sep 2021Sarcomere length non-uniformities occur at all structural levels of skeletal muscles and have been associated with important mechanical properties. Changes in sarcomere...
Sarcomere length non-uniformities occur at all structural levels of skeletal muscles and have been associated with important mechanical properties. Changes in sarcomere length non-uniformities in the nano- and sub-nanometer range have been used to explain muscle properties and contractile mechanisms. Typically, these measurements rely on light microscopy with a limited spatial resolution. One critical aspect in sarcomere length determination is the relatively arbitrary choice of intensity thresholds used to delineate sarcomere structures, such as A-bands or Z-lines. In experiments, these structures are typically distorted, intensity profiles vary, and baselines drift, resulting in asymmetric intensity patterns, causing changes in the centroid location of these structures depending on threshold choice, resulting in changes of sarcomere lengths. The purpose of this study was to determine the changes in (half-) sarcomere lengths associated with small changes in the A-band threshold choice. Sarcomere and half-sarcomere length changes for minute variations in A-band threshold were 28 nm (±28 nm) and 18 nm (±22 nm), respectively, and for the entire feasible range of thresholds across A-bands were 123 nm (±88 nm) and 99 nm (±105 nm), respectively. We conclude from these results that (half-) sarcomere lengths in the nanometer range obtained with light microcopy are noise, and the functional implications associated with such data should be discarded. We suggest that a functional resolution for sarcomere length of 100 nm (0.1 µm) is reasonable and 50 nm (0.05 µm) might be possible under ideal conditions.
Topics: Muscle Contraction; Muscle, Skeletal; Myofibrils; Reproducibility of Results; Sarcomeres
PubMed: 34274869
DOI: 10.1016/j.jbiomech.2021.110628 -
Biochimica Et Biophysica Acta.... Mar 2020The sarcomere is the basic unit of the myofibrils, which mediate skeletal and cardiac Muscle contraction. Two transverse structures, the Z-disc and the M-band, anchor... (Review)
Review
The sarcomere is the basic unit of the myofibrils, which mediate skeletal and cardiac Muscle contraction. Two transverse structures, the Z-disc and the M-band, anchor the thin (actin and associated proteins) and thick (myosin and associated proteins) filaments to the elastic filament system composed of titin. A plethora of proteins are known to be integral or associated proteins of the Z-disc and its structural and signalling role in muscle is better understood, while the molecular constituents of the M-band and its function are less well defined. Evidence discussed here suggests that the M-band is important for managing force imbalances during active muscle contraction. Its molecular composition is fine-tuned, especially as far as the structural linkers encoded by members of the myomesin family are concerned and depends on the specific mechanical characteristics of each particular muscle fibre type. Muscle activity signals from the M-band to the nucleus and affects transcription of sarcomeric genes, especially via serum response factor (SRF). Due to its important role as shock absorber in contracting muscle, the M-band is also more and more recognised as a contributor to muscle disease.
Topics: Actins; Connectin; Humans; Muscle Contraction; Myofibrils; Myosins; Sarcomeres; Serum Response Factor; Transcription, Genetic
PubMed: 30738787
DOI: 10.1016/j.bbamcr.2019.02.003 -
Journal of Biomechanics May 2023The discovery of the giant protein titin, also known as connectin, dates almost half a century back. In this review, I recapitulate major advances in the discovery of... (Review)
Review
The discovery of the giant protein titin, also known as connectin, dates almost half a century back. In this review, I recapitulate major advances in the discovery of the titin filaments and the recognition of their properties and function until today. I briefly discuss how our understanding of the layout and interactions of titin in muscle sarcomeres has evolved and review key facts about the titin sequence at the gene (TTN) and protein levels. I also touch upon properties of titin important for the stability of the contractile units and the assembly and maintenance of sarcomeric proteins. The greater part of my discussion centers around the mechanical function of titin in skeletal muscle. I cover milestones of research on titin's role in stretch-dependent passive tension development, recollect the reasons behind the enormous elastic diversity of titin, and provide an update on the molecular mechanisms of titin elasticity, details of which are emerging even now. I reflect on current knowledge of how muscle fibers behave mechanically if titin stiffness is removed and how titin stiffness can be dynamically regulated, such as by posttranslational modifications or calcium binding. Finally, I highlight novel and exciting, but still controversially discussed, insight into the role titin plays in active tension development, such as length-dependent activation and contraction from longer muscle lengths.
Topics: Connectin; Sarcomeres; Muscle Contraction; Muscle, Skeletal; Muscle Fibers, Skeletal
PubMed: 36989971
DOI: 10.1016/j.jbiomech.2023.111553 -
Journal of Medical Genetics Jan 2017Heart failure (HF) is a major killer with high morbidity and mortality and nearly 37.7 million people are affected by HF globally, making this a global epidemic. HF is a... (Review)
Review
Heart failure (HF) is a major killer with high morbidity and mortality and nearly 37.7 million people are affected by HF globally, making this a global epidemic. HF is a complex pathophysiological syndrome in which the mechanical function of heart for pumping blood is compromised. Cardiac structural and functional abnormalities culminate in decreased cardiac output along with increased intracardiac pressures under resting or stress conditions, leading to HF. Besides the acquired risk factors, the independent role of hereditary and genetic factors in the development, progression and prognosis of HF remains to be established. One of the most common causes of HF is cardiomyopathy and dilated cardiomyopathy and hypertrophic cardiomyopathy are the major forms, transmitted by autosomal dominant inheritance and often result from mutations in single or multiple genes, which predominantly code for proteins present in the cardiac sarcomere. Other inherited forms of cardiomyopathies that can trigger HF are metabolic and mitochondrial cardiomyopathies that result from mutations in proteins involved in fat or carbohydrate metabolism or mitochondrial biogenesis, affecting cardiomyocyte energy balance. Because of the inherent complications in the aetiology of HF, only a small number of genome-wide association studies (GWAS) could be conducted to identify SNPs in genes that are causally related to HF. Recent attempts to conduct GWAS in a focused approach on the HF risk factors led to identification of more SNPs. Initial attempts for gene therapy using adeno-associated viral vectors have not been successful, but more studies are needed to understand the pathophysiological and genetic basis of HF.
Topics: Animals; Cardiomyopathies; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide; Sarcomeres
PubMed: 27872154
DOI: 10.1136/jmedgenet-2016-104308 -
Heart Failure Clinics Apr 2018Sarcomere cardiomyopathies are genetic diseases that perturb contractile function and lead to hypertrophic or dilated myocardial remodeling. Identification of... (Review)
Review
Sarcomere cardiomyopathies are genetic diseases that perturb contractile function and lead to hypertrophic or dilated myocardial remodeling. Identification of preclinical mutation carriers has yielded insights into the earliest biomechanical defects that link pathogenic variants to cardiac dysfunction. Understanding this early molecular pathophysiology can illuminate modifiable pathways to reduce the emergence of overt cardiomyopathy and curb adverse outcomes. Here, the authors review current understandings of how human hypertrophic cardiomyopathy- and hypertrophic dilated cardiomyopathy-linked mutations disrupt the normal structure and function of the sarcomere.
Topics: Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Humans; Sarcomeres
PubMed: 29525643
DOI: 10.1016/j.hfc.2017.12.004 -
Heart (British Cardiac Society) Dec 2014The sarcomere is the principal contractile unit of striated muscle. Mutations in genes encoding sarcomeric proteins are responsible for a range of diseases including... (Review)
Review
The sarcomere is the principal contractile unit of striated muscle. Mutations in genes encoding sarcomeric proteins are responsible for a range of diseases including hypertrophic, dilated and restrictive cardiomyopathies and ventricular non-compaction. The downstream molecular pathways leading to these heterogeneous phenotypes include changes in acto-myosin cross-bridge kinetics, altered mechanosensation, disturbed calcium sensitivity, de-regulated signalling pathways, inefficient energetics, myocardial ischaemia and fibrosis. The elucidation of the genetic causes of cardiomyopathy has helped in understanding the structure and function of the sarcomere and a more detailed knowledge of the sarcomere and its associated proteins has suggested additional gene candidates. The new hope is that these advances will stimulate the discovery of disease-modifying drugs.
Topics: Calcium; Cardiomyopathies; Carrier Proteins; Cell Communication; Genetic Therapy; Homeostasis; Humans; Mutation; Myocardial Contraction; Myofibroblasts; Myosin Heavy Chains; Myosin Light Chains; Sarcomeres; Signal Transduction
PubMed: 25271316
DOI: 10.1136/heartjnl-2014-305645 -
Integrative and Comparative Biology Aug 2018Gaps in our understanding of muscle contraction at the molecular level limit the ability to predict in vivo muscle forces in humans and animals during natural movements.... (Review)
Review
Gaps in our understanding of muscle contraction at the molecular level limit the ability to predict in vivo muscle forces in humans and animals during natural movements. Because muscles function as motors, springs, brakes, or struts, it is not surprising that uncertainties remain as to how sarcomeres produce these different behaviors. Current theories fail to explain why a single extra stimulus, added shortly after the onset of a train of stimuli, doubles the rate of force development. When stretch and doublet stimulation are combined in a work loop, muscle force doubles and work increases by 50% per cycle, yet no theory explains why this occurs. Current theories also fail to predict persistent increases in force after stretch and decreases in force after shortening. Early studies suggested that all of the instantaneous elasticity of muscle resides in the cross-bridges. Subsequent cross-bridge models explained the increase in force during active stretch, but required ad hoc assumptions that are now thought to be unreasonable. Recent estimates suggest that cross-bridges account for only ∼12% of the energy stored by muscles during active stretch. The inability of cross-bridges to account for the increase in force that persists after active stretching led to development of the sarcomere inhomogeneity theory. Nearly all predictions of this theory fail, yet the theory persists. In stretch-shortening cycles, muscles with similar activation and contractile properties function as motors or brakes. A change in the phase of activation relative to the phase of length changes can convert a muscle from a motor into a spring or brake. Based on these considerations, it is apparent that the current paradigm of muscle mechanics is incomplete. Recent advances in our understanding of giant muscle proteins, including twitchin and titin, allow us to expand our vision beyond cross-bridges to understand how muscles contribute to the biomechanics and control of movement.
Topics: Animals; Biomechanical Phenomena; Connectin; Elasticity; Humans; Models, Biological; Muscle Contraction; Muscle, Skeletal; Sarcomeres
PubMed: 29850810
DOI: 10.1093/icb/icy023 -
Journal of Pharmacological and... 2023Understanding translation from preclinical observations to clinical findings is important for evaluating the efficacy and safety of novel compounds. Of relevance to...
Understanding translation from preclinical observations to clinical findings is important for evaluating the efficacy and safety of novel compounds. Of relevance to cardiac safety is profiling drug effects on cardiomyocyte (CM) sarcomere shortening and intracellular Ca dynamics. Although CM from different animal species have been used to assess such effects, primary human CM isolated from human organ donor heart represent an ideal non-animal alternative approach. We performed a study to evaluate primary human CM and have them compared to freshly isolated dog cardiomyocytes for their basic function and responses to positive inotropes with well-known mechanisms. Our data showed that simultaneous assessment of sarcomere shortening and Ca-transient can be performed with both myocytes using the IonOptix system. Amplitude of sarcomere shortening and Ca-transient (CaT) were significantly higher in dog compared to human CM in the basic condition (absence of treatment), while longer duration of sarcomere shortening and CaT were observed in human cells. We observed that human and dog CMs have similar pharmacological responses to five inotropes with different mechanisms, including dobutamine and isoproterenol (β-adrenergic stimulation), milrinone (PDE3 inhibition), pimobendan and levosimendan (increase of Casensitization as well as PDE3 inhibition). In conclusion, our study suggests that myocytes obtained from both human donor hearts and dog hearts can be used to simultaneously assess drug-induced effects on sarcomere shortening and CaT using the IonOptix platform.
Topics: Humans; Dogs; Animals; Myocytes, Cardiac; Calcium; Sarcomeres; Heart Transplantation; Myocardial Contraction; Tissue Donors
PubMed: 37268094
DOI: 10.1016/j.vascn.2023.107278 -
The Journal of Physiology Jul 2021Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving... (Review)
Review
Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving symptoms, but do not prevent or reverse disease progression. Moreover, due to heterogeneity in the clinical manifestations of the disease, patients experience variable outcomes in response to therapeutics. Mechanistically, alterations in calcium handling, sarcomeric disorganization, energy metabolism and contractility participate in HCM disease progression. While some similarities exist, each mutation appears to lead to mutation-specific pathophysiology. Furthermore, these alterations may precede or proceed development of the pathology. This review assesses the efficacy of HCM therapeutics from studies performed in animal models of HCM and human clinical trials. Evidence suggests that a preventative rather than corrective therapeutic approach may be more efficacious in the treatment of HCM. In addition, a clear understanding of mutation-specific mechanisms may assist in informing the most effective therapeutic mode of action.
Topics: Animals; Calcium; Cardiomyopathy, Hypertrophic; Energy Metabolism; Humans; Mutation; Sarcomeres
PubMed: 32822065
DOI: 10.1113/JP279410