Diastole

Figure 3-9: Cartoon of the thin filament with actin and regulatory proteins, Tm and Tn complex, showing conformational differences between inactive state (diastole) and activation (systole). C, COOH terminus; N, NH2 terminus. (From Solaro and Rarick.48 Reproduced with permission from the publisher.)

The sequence of events that ensues when the contractile system is activated by Ca ions entering the cytoplasm as a result of CICR may be summarized as follows46-48 (see Fig. 3-9): In diastole, with low Ca concentration, Tm occupies a position on actin that inhibits interaction between actin and myosin. Strong binding between TnI and Tm appears to be responsible for maintaining this position. In the steric blocking model of Huxley,50 it was hypothesized that in diastole Tm physically blocks any actin-myosin interaction; i.e., crossbridges are detached. It now appears that the situation is more complex.48-51-52 At diastolic Ca concentrations, crossbridges exist in both a truly detached or blocked state and a weakly attached, non-force-producing state. Moreover, it is proposed that weakly attached crossbridges exist in two states, closed and open,, depending on variations in the position of Tm on actin. With activation, Ca ions bind to TnC and cause a complex rearrangement of the Tn complex, with the most important element probably being a switch to strong binding of TnI to TnC rather than to Tm. The latter, in turn, causes a change in the position of Tm on actin that releases inhibition of actin-myosin interaction and, in addition, probably directly influences the kinetics of crossbridge formation by increasing the rate of transitions from the various non-force-producing to force-producing states.

Two other factors appear to be important in this process of thin filament activation. One is nearest-neighbor interactions4748 along the actin monomers, such that binding of Ca to Tn causes the process of crossbridge formation to spread down the thin filament (perhaps to as many as 12 to 14 adjacent monomers). This property appears to be related to activation-induced structural changes in TnT and Tm. The second is strong binding of actin to myosin,48,53,54 which begins to occur once inhibition of the actin-myosin reaction is relieved. In and of itself, strong binding seems to encourage additional thin filament activation. Under most physiologic conditions, systolic Ca concentration does not achieve a level resulting in maximum force and/or shortening; i.e., the muscle is submaximally activated. Cardiac muscle is also highly cooperative; i.e., the relation between Ca concentration and force/shortening between diastolic and maximally activated levels is very steep (Fig. 3-10). This property is thought to be due to both nearest-neighbor interactions and strong actin-myosin binding. Functionally, this means that contractile reserve can be recruited with modest changes in Ca concentration.

Figure 3-10: Relation between log Ca concentration (pCa) and isometric tension in detergent-treated ("skinned") strips of mouse cardiac muscle. R403Q indicates a transgenic animal with a mutation causing hypertrophic cardiomyopathy; control is wild type. Skinning results in loss of integrity of the sarcolemma and all intracellular membranes, leaving sarcomeric proteins intact. In skinned strip, the ionic milieu of the contractile proteins can be manipulated and their behavior studied in isolation from the excitation and ECC systems. Note very steep relation between isometric tension and pCa between relaxing (pCa >7) and fully activating Ca concentrations (pCa 5) in both strips. The relation is shifted to the left in R403Q mice. (From Blanchard E, Seidman C, Seidman JG, et al. Altered crossbridge kinetics in the aMHC403/+ mouse model of familial hypertrophic cardiomyopathy. Circ Res 1999; 84:475. Reprinted with permission of the publisher.)

Regardless of the details of thin filament activation, when Ca binds to TnC, the crossbridge cycle is switched on, and actin and myosin undergo a chemical reaction powered by ATP hydrolysis in which a series of transitions are made from detached/weakly bound states to force-producing states and back.35-36'38'55-59 ATP hydrolysis actually occurs in conjunction with the transition from force production back to detached/weakly bound states. Energy released from hydrolysis of one high-energy phosphate bond is stored in the form of a molecular conformational change in the head of the crossbridge. While the myosin head is strongly bound to actin on the activated thin filament, conformational energy is released, causing the myosin head to rotate slightly as would the oar of a rower seated on the actin filament (Fig. 3-11). This motion generates a force propelling the thin filament along the thick filament toward the center of the sarcomere. The essential light chain appears to function as a lever arm between the thick and thin filaments. This process occurs repeatedly and randomly at millions of actin-myosin crossbridges, causing large-scale force and/or motion generation.

Figure 3-11: Schematic of the mechanical interaction between the myosin head (triangular structure) and actin located on the thin filament. Letter z denotes the distance moved by the thick filament as a result of rotation of the head region (see text). (From Woledge et al.58 Reproduced with permission of the publisher.)

Figure 3-11: Schematic of the mechanical interaction between the myosin head (triangular structure) and actin located on the thin filament. Letter z denotes the distance moved by the thick filament as a result of rotation of the head region (see text). (From Woledge et al.58 Reproduced with permission of the publisher.)

The amount of force and/or shortening that occurs as a result of crossbridge formation is related to the restraints, or load, placed on the muscle.58-60 If no external restraining force is applied (i.e., afterloadis zero), crossbridges propel the filaments at the maximum speed their chemical reactions permit, and a maximum amount of displacement and work are performed with no force generation. This is termed unloaded shortening. If shortening is opposed by an external load, such as during a physiologic contraction, crossbridge motion is slowed, allowing time for force to develop and more crossbridges to find binding sites on the thin filaments. At the other extreme, an isometric contraction in which the muscle is so restrained that there is no external shortening or work (i.e., afterload is greater than can be overcome by the ability to shorten), crossbridge energy is used almost exclusively for force development. This tradeoff between force and motion is reflected in the hyperbolic shape of the force versus velocity relation and the parabolic shape of the power or work versus load relation determined in isolated cardiac muscle Fig.

3-12). There is also a reciprocal relation between load on the muscle and crossbridge cycling rate.58-60 That is, the speed of the chemical reactions driving crossbridge attachment and detachment is sensitive to load and/or the resulting strains or displacements within the sarcomere. The mechanism of this relationship is uncertain, but it is a fundamental property of cardiac muscle that is required for normal function.

Another key determinant of mechanical performance of an activated sarcomere is its initial length, as reflected by the initial length of the muscle (its preload)48-50'61'62 (Fig. 3-13). Force (or shortening) is maximal at an initial sarcomere length of approximately 2.2 Mm and falls off very rapidly below approximately 2 Mm. The ascending length-active tension/force relation is mainly caused by changes in activation of crossbridges as a function of sarcomere length.6162 This is most likely related to the fact that because the sarcomere maintains a constant volume, thick and thin filaments move farther apart at shorter sarcomere lengths.63 The resulting change in geometry causes a decrease in the effective activation at any concentration of Ca; i.e., fewer crossbridges are formed. This length-dependent activation is the primary mechanism at the sarcomere level of the Frank-Starling law of the heart, i.e., the increase in contractile performance as ventricular preload increases. Previously it was thought that the Frank-Starling relation was best explained by changes in thick and thin filament overlap,3555 but the latter is probably a modest contributor at best. Although a descending limb of the length-tension relation is evident in isolated muscle, it does not appear to be present in the intact ventricle.

Frank Starling Law

Figure 3-13: Schematic of relation between sarcomere length and developed tension (or force). Note fall in tension at lengths below approximately 2.2 Mm. At veiy long sarcomere lengths, thick-thin filament overlap is reduced, resulting in descending limb of relation (not observed in ventricle). (Modified from Braunwald E, Ross J Jr, Sonnenblick EH, eds. Mechanisms ofContraction ofthe Normal and Failing Heart. Boston, Little, Brown, 1976:77.)

Sarcomere Length,^

Figure 3-13: Schematic of relation between sarcomere length and developed tension (or force). Note fall in tension at lengths below approximately 2.2 Mm. At veiy long sarcomere lengths, thick-thin filament overlap is reduced, resulting in descending limb of relation (not observed in ventricle). (Modified from Braunwald E, Ross J Jr, Sonnenblick EH, eds. Mechanisms ofContraction ofthe Normal and Failing Heart. Boston, Little, Brown, 1976:77.)

Was this article helpful?

0 0
Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

Get My Free Ebook


Post a comment