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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 Muscle Research and Cell... 2008In healthy human myocardium a tight balance exists between receptor-mediated kinases and phosphatases coordinating phosphorylation of regulatory proteins involved in... (Review)
Review
In healthy human myocardium a tight balance exists between receptor-mediated kinases and phosphatases coordinating phosphorylation of regulatory proteins involved in cardiomyocyte contractility. During heart failure, when neurohumoral stimulation increases to compensate for reduced cardiac pump function, this balance is perturbed. The imbalance between kinases and phosphatases upon chronic neurohumoral stimulation is detrimental and initiates cardiac remodelling, and phosphorylation changes of regulatory proteins, which impair cardiomyocyte function. The main signalling pathway involved in enhanced cardiomyocyte contractility during increased cardiac load is the beta-adrenergic signalling route, which becomes desensitized upon chronic stimulation. At the myofilament level, activation of protein kinase A (PKA), the down-stream kinase of the beta-adrenergic receptors (beta-AR), phosphorylates troponin I, myosin binding protein C and titin, which all exert differential effects on myofilament function. As a consequence of beta-AR down-regulation and desensitization, phosphorylation of the PKA-target proteins within the cardiomyocyte may be decreased and alter myofilament function. Here we discuss involvement of altered PKA-mediated myofilament protein phosphorylation in different animal and human studies, and discuss the roles of troponin I, myosin binding protein C and titin in regulating myofilament dysfunction in cardiac disease. Data from the different animal and human studies emphasize the importance of careful biopsy procurement, and the need to investigate localization of kinases and phosphatases within the cardiomyocyte, in particular their co-localization with cardiac myofilaments upon receptor stimulation.
Topics: Actin Cytoskeleton; Animals; Heart Diseases; Humans; Mice; Myocardial Contraction; Myocytes, Cardiac; Species Specificity
PubMed: 19140019
DOI: 10.1007/s10974-008-9160-y -
Pflugers Archiv : European Journal of... Jul 2011In recent years, it has become evident that heart failure is not solely due to reduced contractile performance of the heart muscle as impaired relaxation is evident in... (Review)
Review
In recent years, it has become evident that heart failure is not solely due to reduced contractile performance of the heart muscle as impaired relaxation is evident in almost all heart failure patients. In more than half of all heart failure patients, diastolic dysfunction is the major cardiac deficit. These heart failure patients have normal (or preserved) left ventricular ejection fraction, but impaired diastolic function evident from increased left ventricular end-diastolic pressure. Perturbations at the cellular level which cause impaired relaxation of the heart muscle involve changes in Ca(2+)-handling proteins, extracellular matrix components, and myofilament properties. The present review discusses the deficits in myofilament function observed in human heart failure and the most likely underlying causal protein changes. Moreover, the consequences of impaired myofilament function for in vivo diastolic dysfunction are discussed taking into account the reported changes in Ca(2+) handling.
Topics: Actin Cytoskeleton; Adrenergic beta-Antagonists; Animals; Calcium; Diastole; Heart Failure; Humans; Myocardial Contraction; Myocardium; Systole; Ventricular Dysfunction, Left; Ventricular Function, Left
PubMed: 21487693
DOI: 10.1007/s00424-011-0960-3 -
Methods in Cell Biology 1997
Review
Topics: Actin Cytoskeleton; Adenoviridae; Animals; Gene Transfer Techniques; Genetic Vectors; Heart; Rats
PubMed: 9379958
DOI: No ID Found -
Archives of Biochemistry and Biophysics Jun 2014
Topics: Actin Cytoskeleton; Animals; Biomechanical Phenomena; Biophysical Phenomena; Humans; Myofibrils; Myosins; Sarcomeres
PubMed: 24890820
DOI: 10.1016/j.abb.2014.05.018 -
Advances in Protein Chemistry 2005
Review
Topics: Actin Cytoskeleton; Connectin; Humans; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Protein Kinases; Sarcomeres
PubMed: 16230110
DOI: 10.1016/S0065-3233(04)71003-7 -
American Journal of Physiology. Cell... Dec 2005A major development in smooth muscle research in recent years is the recognition that the myofilament lattice of the muscle is malleable. The malleability appears to... (Review)
Review
A major development in smooth muscle research in recent years is the recognition that the myofilament lattice of the muscle is malleable. The malleability appears to stem from plastic rearrangement of contractile and cytoskeletal filaments in response to stress and strain exerted on the muscle cell, and it allows the muscle to adapt to a wide range of cell lengths and maintain optimal contractility. Although much is still poorly understood, we have begun to comprehend some of the basic mechanisms underlying the assembly and disassembly of contractile and cytoskeletal filaments in smooth muscle during the process of adaptation to large changes in cell geometry. One factor that likely facilitates the plastic length adaptation is the ability of myosin filaments to form and dissolve at the right place and the right time within the myofilament lattice. It is proposed herein that formation of myosin filaments in vivo is aided by the various filament-stabilizing proteins, such as caldesmon, and that the thick filament length is determined by the dimension of the actin filament lattice. It is still an open question as to how the dimension of the dynamic filament lattice is regulated. In light of the new perspective of malleable myofilament lattice in smooth muscle, the roles of many smooth muscle proteins could be assigned or reassigned in the context of plastic reorganization of the contractile apparatus and cytoskeleton.
Topics: Actin Cytoskeleton; Animals; Calmodulin-Binding Proteins; Microfilament Proteins; Muscle Contraction; Muscle, Smooth; Myosins
PubMed: 16275736
DOI: 10.1152/ajpcell.00329.2005 -
Pflugers Archiv : European Journal of... Jul 2011When cardiac myocytes are stretched by a longitudinal strain, they develop proportionally more active force at a given sub-maximal Ca(2+) concentration than they did at... (Review)
Review
When cardiac myocytes are stretched by a longitudinal strain, they develop proportionally more active force at a given sub-maximal Ca(2+) concentration than they did at the shorter length. This is known as length-dependent activation. It is one of the most important contributors to the Frank-Starling relationship, a critical part of normal cardiovascular function. Despite intense research efforts, the mechanistic basis of the Frank-Starling relationship remains unclear. Potential mechanisms involving myofibrillar lattice spacing, titin-based effects, and cooperative activation have all been proposed. This review summarizes some of these mechanisms and discusses two additional potential theories that reflect the effects of localized strains that occur within and between half-sarcomeres. The main conclusion is that the Frank-Starling relationship is probably the integrated result of many interacting molecular mechanisms. Multiscale computational modeling may therefore provide the best way of determining the key processes that underlie length-dependent activation and their relative strengths.
Topics: Actin Cytoskeleton; Animals; Calcium; Connectin; Mechanotransduction, Cellular; Muscle Proteins; Myocardial Contraction; Myocytes, Cardiac; Protein Kinases; Sarcomeres; Stress, Mechanical
PubMed: 21409385
DOI: 10.1007/s00424-011-0952-3 -
Annals of Biomedical Engineering Aug 2000The syndrome of congestive heart failure (CHF) is an entity of ever increasing clinical significance. CHF is characterized by a steady decrease in cardiac pump function,... (Review)
Review
The syndrome of congestive heart failure (CHF) is an entity of ever increasing clinical significance. CHF is characterized by a steady decrease in cardiac pump function, which is eventually lethal. The mechanisms that underlie the decline in cardiac function are incompletely understood. A central theme in solving the mystery of heart failure is the identification of mechanisms by which the myofilament contractile machine of the myocardium is altered in CHF and how these alterations act in concert with pathways that signal cell growth and death. The cardiac myofilaments are a point of confluence of signals that promote the hypertrophic/failure process. Our hypothesis is that a prevailing hemodynamic stress leads to an increased strain on the myocardium. The increased strain in turn leads to miscues of the normal physiological pathway by which heart cells are signaled to match and adapt the intensity and dynamics of their mechanical activity to prevailing hemodynamic demands. These miscues result in a maladaptation to the stressor and failure of the heart to respond to hemodynamic loads at optimal end diastolic volumes. The result is a vicious cycle exacerbating the failure. Cardiac myofilament activity, the ultimate determinant of cellular dynamics and force, is a central player in the integration and regulation of pathways that signal hypertrophy and failure.
Topics: Actin Cytoskeleton; Animals; Calcium; Cardiomegaly; Disease Progression; Dogs; Heart Failure; Humans; Myocardium; Protein Processing, Post-Translational; Signal Transduction; Stress, Mechanical; Tropomyosin; Troponin; Ventricular Remodeling
PubMed: 11144684
DOI: 10.1114/1.1312189 -
Canadian Journal of Physiology and... Nov 1994Agonist activation enhances smooth muscle myofilament Ca2+ sensitivity. The increased force accompanying receptor stimulation (over Ca2+ alone) requires GTP and is... (Review)
Review
Agonist activation enhances smooth muscle myofilament Ca2+ sensitivity. The increased force accompanying receptor stimulation (over Ca2+ alone) requires GTP and is reversed by GDP beta S, demonstrating a G-protein dependence. Protein kinase C (PKC) activators, such as phorbol esters, mimic and PKC inhibitors block the agonist-induced increase in Ca2+ sensitivity, suggesting a role for PKC in the regulation of Ca2+ sensitivity. Myosin light chain (MLC) phosphorylation levels are transiently increased by agonist stimulation, but steady-state levels of MLC phosphorylation are similar to those in response to Ca2+ alone. Thus, G-protein-mediated inhibition of MLC phosphatase may account for the initial increase in force development but not the increase in steady-state force. In contrast to MLC, calponin phosphorylation levels are maintained during agonist stimulation of intact vascular smooth muscle. We propose that stimulation of smooth muscle by membrane depolarization increases MLC phosphorylation, but as a result of inhibition by unphosphorylated calponin only a portion of the phosphorylated cross bridges attach to actin. Agonist stimulation produces the same steady-state level of MLC phosphorylation but also leads to calponin phosphorylation via a PKC-dependent pathway. Thus, during agonist stimulation, all phosphorylated cross bridges can interact with actin, thereby generating significantly greater levels of force.
Topics: Actin Cytoskeleton; Animals; Calcium; GTP-Binding Proteins; Humans; Muscle, Smooth, Vascular; Receptors, Cell Surface
PubMed: 7767888
DOI: 10.1139/y94-205