In general, force production occurs as follows. First, during muscle relaxation, myosin can bind adenosine triphosphate
(ATP) and hydrolyze it, but cannot use the energy released during hydrolysis to make force (Fig. 6) because of the inhibition of its binding to the thin filament by Tm and Tn. Next, after calcium binding to troponin has released the inhibition of the Tm-Tn complex on the thin filament, an energized myosin crossbridge can attach to the thin filament. This association with actin catalyzes the release of the products of hydrolysis (adenosine 5'-diphosphate [ADP] and inorganic phosphate [Pi]), and a concomitant conformational change of myosin head occurs while it is bound to actin (Fig. 6).
AIT bin (is to myosin causing Hie cross bridge to detach from aclin Fig. 6. Force generation cycle. See text for details. ADP, adenosine 5'-diphosphate; ATP, adenosine triphosphate; Pä, inorganic phosphate.
This conformational change pulls the actin thin filament past the thick filament. Once this is completed, myosin can rebind ATP, which reduces the affinity of myosin for actin and allows for crossbridge detachment. The subsequent hydrolysis of ATP in turn reenergizes the myosin crossbridge and prepares it for the next force-generating cycle. As long as the calcium concentration is high enough to keep the Tm-Tn complexes from blocking the myosin-binding sites on actin, the cycle continues.
It is important to remember that there is a direct connection between the overlap of the thick and thin filaments and the resultant force output developed by cardiac muscle cells. Sarcomere length is defined as the distance from Z line to Z line. In general, when this distance is approx 2.2 ^m, maximal isometric force can be elicited (Fig. 7). If the myocyte is shortened from this length at rest, subsequent force generation decreases because of filament disorder that occurs in overly shortened sarcomeres. In contrast, if the myocyte is stretched, force decreases because of the decrease in overlap of the thick and thin filaments (i.e., a reduced potential for possible crossbridge formations) (Fig. 7). Rest length therefore tends to be slightly shorter than the length at which maximal force is produced. This association between myocyte length and the amount of force that can be generated is known as the length-tension relationship, which underlies the recruitable potential for times when increased contraction force is necessary.
The length of cardiac cells or myocytes is controlled in vivo through their shortening during systole and their stretching during diastole (Fig. 8). That the set point of the length-tension relationship can be tuned in this manner is, in part, the mechanical underpinning for Starling's law of the heart (e.g., stroke volume increases as cardiac filling increases).If cardiac filling adjusts the sarcomere length to a point closer to the plateau of the length-tension relationship (Fig. 7), this length change produces an alignment of the contractile proteins that can then result in greater force production during the next systole. It then also follows that the increased force that can occur during the isovolumic (isometric) phase of systole will result in a greater stroke volume.
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