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Journal of Molecular and Cellular... May 2010The Frank-Starling law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a... (Review)
Review
The Frank-Starling law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a beat-to-beat basis. The main cellular mechanism that underlies this phenomenon is an increase in the responsiveness of cardiac myofilaments to activating Ca(2+) ions at a longer sarcomere length, commonly referred to as myofilament length-dependent activation. This review focuses on what molecular mechanisms may underlie myofilament length dependency. Specifically, the roles of inter-filament spacing, thick and thin filament based regulation, as well as sarcomeric regulatory proteins are discussed. Although the "Frank-Starling law of the heart" constitutes a fundamental cardiac property that has been appreciated for well over a century, it is still not known in muscle how the contractile apparatus transduces the information concerning sarcomere length to modulate ventricular pressure development.
Topics: Actin Cytoskeleton; Animals; Heart; Humans; Models, Biological; Myocardial Contraction; Sarcomeres; Troponin I
PubMed: 20053351
DOI: 10.1016/j.yjmcc.2009.12.017 -
Journal of Applied Physiology... Dec 1999Unaccustomed exercise involving stretch of active muscle at long length causes an immediate loss of tension-generating capacity, a shift of optimum length, and changes... (Review)
Review
Unaccustomed exercise involving stretch of active muscle at long length causes an immediate loss of tension-generating capacity, a shift of optimum length, and changes in excitation-contraction coupling. Eventually, fiber damage may be observed, resulting in pain and tenderness. The subject of this review is the early stage in this process, particularly the cause of the immediate drop in tension. There is strong evidence pointing to sarcomere length instabilities and nonuniformities as important contributors to these changes. The evidence includes the influence of initial length, electron microscopy of rapidly fixed active fibers, the shift in optimum length in single fibers, and the effects of training on sacomere numbers. Experiments using Ca(2+)-sensitive dyes clearly show changes in excitiation-contraction coupling, but cross-species comparisons indicate that these are not always able to explain the consequences seen. We conclude that sarcomere length instabilities provide the most comprehensive explanation of the early consequences of eccentric exercise.
Topics: Animals; Exercise; Humans; Models, Biological; Muscle Tonus; Muscles; Sarcomeres
PubMed: 10601142
DOI: 10.1152/jappl.1999.87.6.2007 -
Archives of Biochemistry and Biophysics Feb 2019Current inotropic therapies improve systolic function in heart failure patients but also elicit undesirable side effects such as arrhythmias and increased intracellular... (Review)
Review
Current inotropic therapies improve systolic function in heart failure patients but also elicit undesirable side effects such as arrhythmias and increased intracellular Ca transients. In order to maintain myocyte Ca homeostasis, the increased cytosolic Ca needs to be actively transported back to sarcoplasmic reticulum leading to depleted ATP reserves. Thus, an emerging approach is to design sarcomere-based treatments to correct impaired contractility via a direct and allosteric modulation of myosin's intrinsic force-generating behavior -a concept that potentially avoids the "off-target" effects. To achieve this goal, various biophysical approaches are utilized to investigate the mechanistic impact of sarcomeric modulators but information derived from diverse approaches is not fully integrated into therapeutic applications. This is in part due to the lack of information that provides a coherent connecting link between biophysical data to in vivo function. Hence, our ability to clearly discern the drug-mediated impact on whole-heart function is diminished. Reducing this translational barrier can significantly accelerate clinical progress related to sarcomere-based therapies by optimizing drug-dosing and treatment duration protocols based on information obtained from biophysical studies. Therefore, we attempt to link biophysical mechanical measurements obtained in isolated cardiac muscle and in vivo contractile function.
Topics: Animals; Cardiotonic Agents; Heart Failure; Humans; Myocardial Contraction; Myocardium; Sarcomeres; Translational Research, Biomedical
PubMed: 30576628
DOI: 10.1016/j.abb.2018.12.021 -
Disease Markers 2020The sarcomeric proteins control the movement of cells in diverse species, whereas the deregulation can induce tumours in model organisms and occurs in human carcinomas.... (Review)
Review
The sarcomeric proteins control the movement of cells in diverse species, whereas the deregulation can induce tumours in model organisms and occurs in human carcinomas. Sarcomeric proteins are recognized as oncogene and related to tumor cell metastasis. Recent insights into their expressions and functions have led to new cancer therapeutic opportunities. In this review, we appraise the evidence for the sarcomeric proteins as cancer genes and discuss cancer-relevant biological functions, potential mechanisms by which sarcomeric proteins activity is altered in cancer.
Topics: Gene Expression Regulation, Neoplastic; Humans; Muscle Proteins; Neoplasm Metastasis; Neoplasms; Sarcomeres
PubMed: 32670437
DOI: 10.1155/2020/8885286 -
Journal of Biomechanics 1991Animal muscles generate forces and induce movements at desirable rates. These roles are interactive and must be considered together. Performance of the organism and... (Review)
Review
Animal muscles generate forces and induce movements at desirable rates. These roles are interactive and must be considered together. Performance of the organism and survival of the species also involve potential optimization of control and of energy consumption. Further, individual variability arising partly via ontogeny and partly from phylogenetic history often has pronounced and sometime conflicting effects on structures and their uses. Hence, animal bodies are generally adequate for their tasks rather than being elegantly matched to them. For muscle, matching to role is reflected at all levels of muscular organization, from the nature of the sarcoplasm and contractile filaments to architectural arrangements of the parts and whole of organs. Vertebrate muscles are often analyzed by mapping their placement and then "explaining" this on the basis of currently observed roles. A recent alternative asks the obverse; given a mass of tissue that may be developed and maintained at a particular cost, what predictions do physical principles permit about its placement. Three architectural patterns that deserve discussion are the classical arrangement of fibers in pinnate patterns, the more recent assumption of sarcomere equivalence, and the issue of compartmentation. All have potential functional implications. 1. The assumption of equivalence of the sarcomeres of motor units allows predictions of the fiber length between sites of origin and insertion. In musculoskeletal systems that induce rotation, the observed (but not the pinnation-associated) insertion angle will differ with the radial lines on which the fibers insert. In a dynamic contraction inducing rotation, a shift of moment arm has no effect for muscles of equal mass. 2. Classical pinnate muscles contain many relatively short fibers positioned in parallel but at an angle to the whole muscle, reducing the per fiber force contribution. However, the total physiological cross-section and total muscle force are thus increased relative to arrangements with fibers parallel to the whole muscle. Equivalent muscles may be placed in various volumetric configurations matching other demands of the organism. The loss of fiber force due to (pinnate, not equivalent) angulation is compensated for by the reduced shortening of fibers in multipinnate arrays. 3. Compartmentation, i.e., the subdivision of muscles into independently controlled, spatially discrete volumes, is likely ubiquitous. Differential activation of the columns of radial arrays may facilitate change of vector and with this of function. Compartmentation is apt to be particularly important in strap muscles with short fiber architecture; their motor units generally occupy columnar, rather than transversely stacked, subdivisions; this may affect recovery from fiber atrophy and degeneration.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Biomechanical Phenomena; Muscle Contraction; Muscles; Myofibrils; Sarcomeres
PubMed: 1791182
DOI: 10.1016/0021-9290(91)90377-y -
The Journal of Biological Chemistry Mar 2011Oxidative stress is common in many clinically important cardiac disorders, including ischemia/reperfusion, diabetes, and hypertensive heart disease. Oxidative stress... (Review)
Review
Oxidative stress is common in many clinically important cardiac disorders, including ischemia/reperfusion, diabetes, and hypertensive heart disease. Oxidative stress leads to derangements in pump function due to changes in the expression or function of proteins that regulate intracellular Ca(2+) homeostasis. There is growing evidence that the cardiodepressant actions of reactive oxygen species (ROS) also are attributable to ROS-dependent signaling events in the sarcomere. This minireview focuses on myofilament protein post-translational modifications induced by ROS or ROS-activated signaling enzymes that regulate cardiac contractility.
Topics: Animals; Calcium; Heart Diseases; Homeostasis; Humans; Myocardial Contraction; Myocardium; Oxidative Stress; Reactive Oxygen Species; Sarcomeres; Signal Transduction
PubMed: 21257753
DOI: 10.1074/jbc.R110.175489 -
The Journal of Clinical Investigation Jan 2024Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy...
Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM). However, the molecular mechanisms by which TTNtv mutations induce DCM are controversial. Here, we studied 127 clinically identified DCM human cardiac samples with next-generation sequencing (NGS), high-resolution gel electrophoresis, Western blot analysis, and super-resolution microscopy in order to dissect the structural and functional consequences of TTNtv mutations. The occurrence of TTNtv was found to be 15% in the DCM cohort. Truncated titin proteins matching, by molecular weight, the gene sequence predictions were detected in the majority of the TTNtv+ samples. Full-length titin was reduced in TTNtv+ compared with TTNtv- samples. Proteomics analysis of washed myofibrils and stimulated emission depletion (STED) super-resolution microscopy of myocardial sarcomeres labeled with sequence-specific anti-titin antibodies revealed that truncated titin was structurally integrated into the sarcomere. Sarcomere length-dependent anti-titin epitope position, shape, and intensity analyses pointed at possible structural defects in the I/A junction and the M-band of TTNtv+ sarcomeres, which probably contribute, possibly via faulty mechanosensor function, to the development of manifest DCM.
Topics: Humans; Cardiomyopathy, Dilated; Connectin; Heart; Sarcomeres
PubMed: 37962957
DOI: 10.1172/JCI169753 -
Journal of Molecular and Cellular... Jan 2017Sarcomere assembly is a highly orchestrated and dynamic process which adapts, during perinatal development, to accommodate growth of the heart. Sarcomeric components,...
Sarcomere assembly is a highly orchestrated and dynamic process which adapts, during perinatal development, to accommodate growth of the heart. Sarcomeric components, including titin, undergo an isoform transition to adjust ventricular filling. Many sarcomeric genes have been implicated in congenital cardiomyopathies, such that understanding developmental sarcomere transitions will inform the aetiology and treatment. We sought to determine whether Thymosin β4 (Tβ4), a peptide that regulates the availability of actin monomers for polymerization in non-muscle cells, plays a role in sarcomere assembly during cardiac morphogenesis and influences adult cardiac function. In Tβ4 null mice, immunofluorescence-based sarcomere analyses revealed shortened thin filament, sarcomere and titin spring length in cardiomyocytes, associated with precocious up-regulation of the short titin isoforms during the postnatal splicing transition. By magnetic resonance imaging, this manifested as diminished stroke volume and limited contractile reserve in adult mice. Extrapolating to an in vitro cardiomyocyte model, the altered postnatal splicing was corrected with addition of synthetic Tβ4, whereby normal sarcomere length was restored. Our data suggest that Tβ4 is required for setting correct sarcomere length and for appropriate splicing of titin, not only in the heart but also in skeletal muscle. Distinguishing between thin filament extension and titin splicing as the primary defect is challenging, as these events are intimately linked. The regulation of titin splicing is a previously unrecognised role of Tβ4 and gives preliminary insight into a mechanism by which titin isoforms may be manipulated to correct cardiac dysfunction.
Topics: Animals; Connectin; Echocardiography; Heart; Hemodynamics; Male; Mice; Mice, Knockout; Myocardial Contraction; Myocardium; Myocytes, Cardiac; RNA Splicing; Sarcomeres; Thymosin
PubMed: 27914791
DOI: 10.1016/j.yjmcc.2016.10.010 -
Biochimica Et Biophysica Acta.... Aug 2017Pre-mRNA splicing is an important biological process that allows production of multiple proteins from a single gene in the genome, and mainly contributes to protein... (Review)
Review
Pre-mRNA splicing is an important biological process that allows production of multiple proteins from a single gene in the genome, and mainly contributes to protein diversity in eukaryotic organisms. Alternative splicing is commonly governed by RNA binding proteins to meet the ever-changing demands of the cell. However, the mis-splicing may lead to human diseases. In the heart of human, mis-regulation of alternative splicing has been associated with heart failure. In this short review, we focus on alternative splicing of sarcomeric genes and review mis-splicing related heart failure with relatively well studied Sarcomeric genes and splicing mechanisms with identified regulatory factors. The perspective of alternative splicing based therapeutic strategies in heart failure has also been discussed.
Topics: Alternative Splicing; Animals; Heart Failure; Humans; Myocardium; RNA Precursors; RNA-Binding Proteins; Sarcomeres
PubMed: 27825848
DOI: 10.1016/j.bbadis.2016.11.008 -
Experimental Physiology Jul 2021What is the central question of this study? In the papillary muscle from type I diabetic rats, does diabetes-associated altered ventricular function result from changes...
NEW FINDINGS
What is the central question of this study? In the papillary muscle from type I diabetic rats, does diabetes-associated altered ventricular function result from changes of acto-myosin interactions and are these modifications attributable to a possible sarcomere rearrangement? What is the main finding and its importance? For the first time, we showed that type-I diabetes altered sarcomeric ultrastructure, as seen by transmission electron microscopy, consistent with physiological parameters. The diabetic condition induced slower timing parameters, which is compatible with a diastolic dysfunction. At the sarcomeric level, augmented β-myosin heavy chain content and increased sarcomere length and crossbridges' number preserve myocardial stroke and could concur to maintain the ejection fraction.
ABSTRACT
We investigated whether diabetes-associated altered ventricular function, in a type I diabetes animal model, results from a modification of acto-myosin interactions, through the in vitro recording of left papillary muscle mechanical parameters and examination of sarcomere morphology by transmission electron microscopy (TEM). Experiments were performed on streptozotocin-induced diabetic and age-matched control female Wistar rats. Mechanical isometric and isotonic indexes and timing parameters were determined. Using Huxley's equations, we calculated mechanics, kinetics and energetics of myosin crossbridges. Sarcomere length and A-band length were measured on TEM images. Type I and III collagen and β-myosin heavy chain (MHC) expression were determined by immunoblotting. No variation in resting and developed tension or maximum extent of shortening was evident between groups, but diabetic rats showed lower maximum shortening velocity and prolonged timing parameters. Compared to controls, diabetics also displayed a higher number of crossbridges with lower unitary force. Moreover, no change in type I and III collagen was associated to diabetes, but pathological rats showed a two-fold enhancement of β-MHC content and longer sarcomeres and A-band, detected by ultrastructural morphometry. Overall, these data address whether a preserved systolic function accompanied by an altered diastolic phase results from a recruitment of super-relaxed myosin heads or the phosphorylation of the regulatory light chain site in myosin. Although the early signs of diabetic cardiomyopathy were well expressed, the striking finding of our study was that, in diabetics, sarcomere modification may be a possible compensatory mechanism that preserves systolic function.
Topics: Animals; Diabetes Mellitus, Experimental; Female; Myocardial Contraction; Rats; Rats, Wistar; Sarcomeres; Streptozocin
PubMed: 33977604
DOI: 10.1113/EP089000