Klenchin, J. Deacon, A. Combs, L. Leinwand, and I. The actin-binding, converter, and lever-arm domains are indicated. The length of the globular head from the actin-binding domain to the end of the converter is 9 nm, and from the end of the converter to the end of the lever arm is 8 nm.
The shape of the curve depends on how much force the contractile machinery can produce. At any velocity along the curve, the ensemble force of the system matches the equal and opposite load imposed. Power output is the force times the velocity at every point along the curve dashed line , solid circles.
Gray zone Region of high power output. The reverse is expected for the hypocontractile-causing mutant forms solid blue F-v curve ; dashed blue power curve. Hypercontractile-causing mutations can also, of course, lead to changes in both ensemble force and velocity. To see this figure in color, go online. There are, however, additional regulatory elements, such as myosin binding protein C and titin; mutations in myosin binding protein C are a frequent cause of HCM 4 and mutations in titin are a prevalent cause of DCM 31— Power is the product of force and velocity of contraction, and the force-velocity curve is a fundamental functional aspect of cardiac muscle function 34 Fig.
The force axis on this curve is related to the load on the muscle; the force the muscle produces must overcome the load. Ventricular function is influenced by two types of loads that are applied to cardiac muscle.
One is the preload, which is the load applied by the volume of blood in the left ventricle that results in stretching of the myofibers before the initiation of ejection. The afterload is the primary load that the heart needs to overcome to eject blood out of the left ventricle, and is also the load mentioned in the F-v curves shown in Fig. This review focuses on the biomechanical aspects of the myosin-actin interaction. Its regulation by thin filament components is also critical in determining myocardial contractility, as briefly discussed below.
HCM patients present with clinical features of hyperdynamic ventricular function, as suggested by physical exam and echocardiographic findings 4. Conversely, the clinical features of DCM patients are characterized by reduced systolic function causing hypoperfusion of the body circulation.
Thus, the simplest view is that there are two mechanistic buckets for changes in power output at the molecular level, mutations resulting in an increase in power hypercontractile and a decrease in power hypocontractile , and small molecule therapies could be directed toward either reducing the power output or increasing it, respectively, to normalize the effect of the mutation and then allowing the heart to remodel. Life, however, is not that simple. First of all, the relationships between the hypercontractile HCM heart and the hypocontractile DCM heart with the fundamental power outputs of the contractile molecular machinery making up the sarcomere, at the earliest stages before apparent clinical symptoms, remain to be clarified.
Thus, the hypothesis that HCM is hypercontractile at the fundamental molecular level of a sarcomere whereas DCM is hypocontractile—although a common view for reviews, see the literature 36—40 —remains to be established as a general paradigm.
Consistent with this hypothesis, however, studies of mouse models of HCM and DCM and with purified mouse cardiac myosin suggest that HCM cardiomyopathy mutations cause hypercontractility whereas DCM cardiomyopathy mutations cause hypocontractility 41, However, these samples were obtained from patients undergoing palliative surgery for severe hypertrophy and contained severely diseased myocardium with a multitude of secondary changes that make determining the primary effects of the mutations on the molecular biomechanics of the sarcomere difficult, if not impossible.
As a major advance, Srikakulam and Winkelmann 45 solved the problem of mammalian myosin expression using adenovirus expression in the mouse myogenic cell line C2C They have characterized the involvement of a number of chaperones involved in mammalian skeletal myosin folding, including heat shock protein 90 Hsp90 , constitutively expressed heat shock-related protein 70 Hsc70 , and Unc45b 45, The C2C12 expression system has been adapted to the cardiomyopathy problem by Deacon et al.
Having the human reconstituted system now provides an opportunity to understand the detailed effects of these mutations on the power output of the fundamental unit of the human cardiac muscle, the sarcomere. We are using a variety of assays, including loaded in vitro motility assays and single-molecule analyses with a dual-beam laser trap. Because there are currently insufficient data to conclude that HCM mutations generally cause hypercontractile sarcomeres and DCM mutations generally cause hypocontractile sarcomeres at the earliest stages before apparent clinical symptoms, I will simply refer throughout to mutations causing increased power output by the sarcomere hypercontractile versus those causing decreased power output hypocontractile.
Furthermore, I will focus on mutations that cause hypercontractility to explain the changes in the actin-activated myosin chemomechanical cycle that can lead to increased power output. I will then discuss available assays for exploring this space, and how they can be used to search for appropriate small molecule therapies. All that I discuss below applies to the hypocontractile mutations as well, but in reverse.
An increase in power output could result from an increase in the ensemble force red solid line produced by the muscle, or an increase in velocity of contraction green solid line at various loads. A combination of change in force and change in velocity is also possible. Note that small changes in the F-v curve result in significant changes in power output. Load in Fig. I refer to the force produced by the cardiac muscle as the ensemble force, because each myosin head is an independent force generator with its own intrinsic force, and the total force produced in the muscle is the intrinsic force times the number of heads in the ensemble that are in a force-producing state, as described in more detail below.
From a therapeutic point of view, it may be beneficial to target the increased power output caused by hypercontractile-causing mutations by developing small molecule inhibitors of the power output, regardless of whether those molecules reduce the force or the velocity. Furthermore, one could target any of the members of the fundamental six-component contractile system to do so. An agent is likely to be beneficial simply by bringing the F-v curve back down toward normal without worrying about its detailed shape.
Ideal small molecule therapies, however, would normalize the F-v curve across all loads, bringing the mutant curves in line with the wild-type F-v relationship. Is this possible? Fortunately, the contractile system is one of the most thoroughly studied enzyme systems in biology, so our deep knowledge of the biochemical and biophysical parameters involved allows the creation of appropriate assays for identifying small molecules that independently modulate F or v.
The actin-activated myosin chemomechanical cycle can be divided into two fundamental parts:. The weakly-bound state of the myosin heads yellow , Fig. Pi bound to the active site of the motor domain; and. The actin-activated myosin chemomechanical cycle. Step 1: ATP binding to the strongly-bound myosin head dissociates it from the actin. Step 2: ATP hydrolysis is associated with locking the weakly-bound head into a prestroke configuration. Step 3 a and b : Rebinding of the head to actin in a strongly-bound state is associated with Pi release from the active site.
The head is now in a strongly-bound force-producing state and cannot bind ATP until the ADP is released from the active site. Modified from Lymn and Taylor 95, The strongly-bound state that is force-producing red , Fig.
I will use the value 0. As noted above, every head acts as an independent force generator, producing its own intrinsic force f. Therefore, the ensemble force F e produced by the contractile apparatus is the intrinsic force of each head multiplied by the total number of heads that are bound in a force-producing state,. Kinetically, ATP binding is extremely fast, as is the resultant dissociation of the myosin-ATP complex from the actin.
After the myosin head dissociates from actin, hydrolysis is generally rapid Step 2 , Fig. For cardiac myosin, it is thought to favor the ADP. The rate of this weak-to-strong transition is generally the rate-limiting step in the entire cycle and therefore determines the k cat , or maximum rate of the myosin ATPase activity at saturating actin concentration although the ATP hydrolysis rate is slow enough for cardiac myosin to potentially play a role in determination of the k cat.
Kinetically, this bimolecular interaction of myosin with actin in the sarcomere is limited by two factors. One is the kinetic efficiency of the system or how many collisions need to happen before a productive collision occurs.
The other is that in the sarcomere, the actin thin filament helical period is different from that of the myosin head arrangement along the thick filament, and therefore, at any particular amount of overlap of the thin and thick filaments, only selected myosin heads see the actin monomer to which it wants to bind in an orientation that will allow a productive collision Fig.
In other words, the catalytic efficiencies for individual heads in the sarcomere, at any particular amount of overlap of the thin and thick filaments, are different, and are constantly changing during contraction as the two filaments slide past one another. This is in contrast to in vitro experiments with purified proteins in solution, which provide a measure of k cat for the actin-activated myosin ATPase at saturating actin concentration in which all heads behave similarly. But it is worth keeping in mind that in the sarcomere, at any particular amount of overlap of the thin and thick filaments, some heads are structurally more favorably positioned for interaction with actin in contrast to in solution in vitro, limited only by the catalytic efficiency of the collision complex, whereas other heads are restricted by an unfavorable orientation for actin interaction compared to in solution in vitro.
The structures of the actin filament, myosin thick filament, and their packing in the sarcomere, drawn to scale. The myosin filament, approximately three times thicker, consists of myosin heads arranged in a three-start right-handed helix. The end-on view is shown on the right. The periodicities of the actin filament and myosin heads in the thick filament are not related. The packing is quite dense with heads very near the actin even in the resting state.
Note that while Fig. Thus, in the presence of physiological concentrations of ATP, the rate of ADP release determines the mean time that the head remains in a strongly bound state t s. Hypercontractile-causing mutations that result in a change in F e solid red line , Fig.
There are therefore only a few hypothetical mechanistic buckets for changing the ensemble force and thus altering the power output. However, power output can also be increased by an increase in velocity. For simplicity here, consider that hypercontractile-causing mutations that alter velocity solid green line , Fig.
Changing d or t s represent two hypothetical mechanistic buckets for affecting the velocity and thus altering the power output. So, there are at least four hypothetical mechanistic buckets for causing an increase in power output by hypercontractile-causing mutations, changes in f , t s , t c , or d or some combination of these.
Alterations in t s are interesting because such changes have opposing effects on velocity and ensemble force. Thus, an increase in t s can lead to a decrease in velocity decreased power but an increase in duty ratio increased power , and a decrease in t s can lead to the reverse.
Thus, a hypercontractile-causing mutation that leads primarily to a decrease in t s would resemble the green solid line curve in Fig. The converse considerations apply to the same three mechanistic buckets that can lead to the reduced power output of hypocontractile-causing mutations. How many myosin heads are in a strongly-bound state to an individual actin filament in the sarcomere at any given time? And how many times does an individual head go through its chemomechanical cycle in the course of a single contraction of the cardiac muscle systole?
The answers surprised me and require a reasonably accurate view of the structure of the sarcomere. There are many published drawings of a sarcomere to illustrate the sliding filament model of muscle contraction, but they seldom depict the actin and myosin drawn to scale, and the conventional textbook schematic representations show a much higher extent of shortening than occurs in human cardiac sarcomeres.
The actin filaments in cardiac muscle have been reported to be 0. Schematic description of a cardiac sarcomere drawn to scale. Top A sarcomere is depicted at its resting length just beginning its contraction.
Note the myosin molecules are depicted as single-headed for simplicity. A duty ratio of 0. The cardiac myosin thick filaments are 1. The bare zone where there are no heads is 0. Reconstructions from electron micrographs have revealed perturbations in axial displacement, azimuthal displacement, and tilt of the heads in the cardiac myosin filament, but the radial perturbation of myosin heads is minor There are three myosin molecules per If we simplify the thick filament helical array to a cylinder, myosin heads along one edge are spaced A common packing pattern has each actin filament in the sarcomere surrounded by three myosin thick filaments, which are arranged in a hexameric cross-sectional pattern Fig.
In this arrangement, Because the myosin thick filament in a half-sarcomere is nm long, nm of which is bare zone without heads, and there are three double-headed myosin molecules every Other heads that are nearby could also potentially interact, making the number of heads potentially available for interaction with one actin filament somewhat larger Figs.
Note that the periodicity of heads along the thick filament is different from the periodicity of the actin filament nm pseudo-repeat , insuring asynchronous binding of myosin heads to get a smooth contraction. Although the myosin molecule is two-headed, as depicted in Fig. In a key study, Cooke and Franks in 65 showed that single-headed myosin generates one-half as much tension per molecule as does double-headed myosin. These experiments conclusively showed that the two heads of myosin interact independently with actin in the generation of tension, with no evidence of cooperativity between the heads.
These experiments also showed that all the heads in the native two-headed myosin configuration are available for producing force because twice the force was observed with the two-headed myosin than with the single-headed myosin. Therefore, in my discussions below, I will consider all the myosin heads two times the number of myosin molecules as being available for force production. Another simplification in the two-dimensional drawing of Fig. Despite these simplifications, several key features become apparent from this figure, as described in more detail below:.
The problem often spreads to the right ventricle and then to the atria. As the heart chambers dilate, the heart muscle doesn't contract normally and cannot pump blood very well.
As the heart becomes weaker heart failure can occur. Common symptoms of heart failure include shortness of breath, fatigue and swelling of the ankles, feet, legs, abdomen and veins in the neck. Dilated cardiomyopathy also can lead to heart valve problems , arrhythmias irregular heartbeats and blood clots in the heart. Often, cause of dilated cardiomyopathy isn't known. Up to one-third of the people of those who have it inherit it from their parents. Hypertrophic cardiomyopathy occurs when the muscle mass of the left ventricle of the heart is larger than normal, or the wall between the two ventricles septum becomes enlarged and obstructs the blood flow from the left ventricle.
Dilated cardiomyopathy is the most frequent form of non-ischemic cardiomyopathy. The cavity of the heart is enlarged and stretched cardiac dilation causing the heart to become weak and not pump normally. Restrictive cardiomyopathy, the least common type of cardiomyopathy in the US, occurs when the myocardium of the ventricles becomes excessively rigid, and the filling of the ventricles with blood between heart beats is impaired.
Your physician will determine the best medication s to provide you to help with the symptoms you are experiencing. Alcohol septal ablation. Cardiologists specializing in alcohol septal ablation treatment use a catheter to inject alcohol into the specific area of the heart to destroy the thickened part of the heart muscle. It can deliver an electric shock to control an abnormal rhythm.
An implanted pacemaker may be recommended to coordinate the contractions between the left and right sides of your heart. In a small number of cases, a heart transplant may be necessary. If cardiomyopathy is properly treated and controlled, many people with the condition can manage with just a few changes to their normal lifestyle.
Some people might need to make major adjustments to their lifestyle. If you are told to limit or avoid some sports or activities, there are other light-to-moderate physical activities that can help you to remain healthy and avoid other heart problems. It is important to talk to your cardiologist about how you can live a healthy, active lifestyle without risking further complications.
A dietitian can advise you about healthy eating. They can provide tips to manage your fluid and salt intake to help your heart. Giving up alcohol completely is a good idea. Losing weight can also help relieve symptoms by reducing the burden on your heart. Find someone you can turn to for emotional support like a family member, friend, doctor, mental health worker or support group. Talking about your challenges and feelings could be an important part of your journey to recovery.
To find useful services to help you on your journey with heart disease, see our services and resources listing. Donate now. Heart disease Conditions A-Z Cardiomyopathy. What is cardiomyopathy? Types There are four types of cardiomyopathy. Dilated congestive cardiomyopathy This is the most common form of cardiomyopathy.
Hypertrophic cardiomyopathy HCM HCM occurs because the heart's walls become thickened, which makes it harder for the heart to pump blood.
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