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Chapter 4: PRINCIPLES OF MOLECULAR CARDIOLOGY THE SARCOMERE AND CARDIAC CONTRACTION

Cardiac myocytes are large cells of up to 120 Mm in length.They are joined together in a syncytium. The sarcolemma surrounding the myocyte through the intercalated disk joins to adjacent cells and invaginates into the myofibril through the T-tubules. Cardiac muscle is composed of fibers, which in turn are composed of myofibrils. The myofibril has a periodicity imparted to it by the sarcomere, which is the working unit of contraction. The sarcomeres are joined in series with each other via the Z-lines. The sarcomere is composed of many proteins, with myosin and actin being the predominant proteins comprising the thick and thin filaments, respectively. Two regulatory proteins are attached to the actin filament-tropomyosin and the troponins C, T, and I-and two myosin light chain molecules are attached to the myosin heavy chains. The sarcomeres comprise about 50 percent of the mass of the cardiac myocyte and, depending on the state of contraction, vary from 1.6 to 2.2 Mm in length, as shown in Fig. 4-16. The specific molecular functions of the proteins that comprise the sarcomere are now beingcarefully elucidated by the discovery of mutations that are responsible for inherited diseases, particularly familial hypertrophic cardiomyopathy (FHCM). It is now recognized that FHCM is essentially a disease of the sarcomere, with eight sarcomeric genes having being identified exhibiting over 100 mutations that cause hypertrophic cardiomyopathy (HCM).

Hcm Sarcomere Mutation

Figure 4-16: Relationship of sarcomere length and tension generated during isometric contraction of striated muscle. Maximum tension is generated at sarcomere lengths that allow maximum interaction of myosin heads and actin filaments (positions 2 and 3). If the sarcomere length is too short (positions 4 and 5), actin filaments overlap one another and prevent optimal interaction with myosin heads. (From Darnell J, Lodish H, Baltimore D, eds. Molecular Cell Biology. New York: Scientific American Books, W. H. Freeman; 1990. Reproduced with permission from the publisher.)

Figure 4-16: Relationship of sarcomere length and tension generated during isometric contraction of striated muscle. Maximum tension is generated at sarcomere lengths that allow maximum interaction of myosin heads and actin filaments (positions 2 and 3). If the sarcomere length is too short (positions 4 and 5), actin filaments overlap one another and prevent optimal interaction with myosin heads. (From Darnell J, Lodish H, Baltimore D, eds. Molecular Cell Biology. New York: Scientific American Books, W. H. Freeman; 1990. Reproduced with permission from the publisher.)

The Contractile Proteins

The proposed mechanism whereby the actin filaments slide over the myosin filaments and induce shortening or contraction is illustrated in B+;Bi Fig. 4-17. Cardiac contraction and relaxation are regulated in part by calcium. The sarcoplasmic reticulum (SR) induces contraction by releasing calcium and induces relaxation by sequestering it. Hydrolysis of ATP at a rate of one molecule per myosin head is required for each cycle, as the actin filament moves a distance of about 7 nm. In the relaxed state, myosin is prohibited from binding to actin by the presence of tropomyosin and troponin, which block the binding site for myosin. Myosin has minimal ATPase activity in the absence of actin; nevertheless, it does induce some hydrolysis of ATP to ADP and Pi. Systolic contraction is induced by calcium. Calcium released from the SR binds to troponin C, which induces a slight movement of tropomyosin that exposes the binding site on actin for myosin. The resulting binding of actin to myosin increases the ATPase activity of myosin by about 200-fold, which hydrolyzes the ATP to ADP. The ADP is released from the head of the myosin, which further enhances the binding of myosin to actin. The head of the myosin, which is oriented at a 90° angle to the actin, flexes to a 45° angle and in so doing moves the actin filaments closer together. Subsequently, the calcium is again sequestered by the SR, and ATP binds to the myosin head, which inhibits binding to the actin, relaxes the sarcomere, and reinitiates diastole (B*;B; Fig. 4-18). Using high-intensity x-ray from a synchrotron, it has been possible to follow the changes in muscle-diffraction patterns during muscle contraction. The increase in cytosolic calcium and tropomyosin movement occur 17 ms after a muscle is stimulated. The myosin head attaches to actin after about 25 ms, and the tension is generated after about 40 ms (see also Chap.

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