Cardiac Muscle

Basic Organization of Cardiac Muscle Cells

Cardiac muscle cells are much smaller than skeletal muscle cells. Typically, cardiac muscle cells measure 10 µm in diameter and approximately 100 µm in length. As shown in Fig. 13.1A , cardiac cells are connected to each other through intercalated disks, which include a combination of mechanical junctions and electrical connections. The mechanical connections, which keep the cells from pulling apart when contracting, include the fascia adherens and desmosomes. Gap junctions between cardiac muscle cells, on the other hand, provide electrical connections between cells to allow propagation of the action potential throughout the heart. Thus the arrangement of cardiac muscle cells within the heart is said to form an electrical and mechanical syncytium that allows a single action potential (generated within the sinoatrial node) to pass throughout the heart so that the heart can contract in a synchronous, wave-like manner. Blood vessels course through the myocardium.

The basic organization of thick and thin filaments in cardiac muscle cells is comparable with that in skeletal muscle (see Chapter 12 ). Electron microscopy reveals repeating light and dark bands that represent I bands and A bands, respectively (see Fig. 13.1B and Chapter 12 , Fig. 12.3 ). Thus cardiac muscle is classified as a striated muscle. The Z line transects the I band and represents the point of attachment of the thin filaments. The region between two adjacent Z lines represents the sarcomere, which is the contractile unit of the muscle cell. The thin filaments are composed of actin, tropomyosin, and troponin and extend into the A band. The A band is composed of thick filaments, along with some overlap of thin filaments. The thick filaments are composed of myosin and extend from the center of the sarcomere toward the Z lines.

Myosin filaments are formed by a tail-to-tail association of myosin molecules in the center of the sarcomere, followed by a head-to-tail association as the thick filament extends toward the Z lines. Thus the myosin filament is polarized and poised for pulling the actin filaments toward the center of the sarcomere. A cross-sectional view of the sarcomere near the end of the A band shows that each thick filamentis surrounded by six thin filaments, and each thin filament receives cross-bridge attachments from three thick filaments. This complex array of thick and thin filaments is characteristic of both cardiac and skeletal muscle and helps stabilize the filaments during muscle contraction (see Fig. 12.3B for the hexagonal array of thick and thin filaments in the sarcomere of striated muscle).

Several proteins may contribute to the organization of the thick and thin filaments, including meromyosin and C protein (in the center of the sarcomere), which appear to serve as a scaffold for organization of the thick filaments. Similarly, nebulin extends along the length of the actin filament and may serve as a scaffold for the thin filament. The actin filament is anchored to the Z line by α-actinin, whereas the protein tropomodulin resides at the end of the actin filament and regulates the length of the thin filament. These proteins are present in both cardiac and skeletal muscle cells.

The thick filaments are tethered to the Z lines by a large elastic protein called titin. Although titin was postulated to tether myosin to the Z lines and thus prevent overstretching of the sarcomere, there is evidence indicating that titin may participate in cell signaling (perhaps by acting as a stretch sensor and thus modulating protein synthesis in response to stress). Such signaling by titin has been observed in both cardiac and skeletal muscle cells. Moreover, genetic defects in titin result in atrophy of both cardiac and skeletal muscle cells and may contribute to both cardiac dysfunction and skeletal muscle dystrophies (termed titinopathies ). Titin is also thought to contribute to the ability of cardiac muscle to increase force upon stretch (discussed in the later section “Stretch”).

Although both cardiac muscle and skeletal muscle contain an abundance of connective tissue, there is more connective tissue in the heart. The abundance of connective tissue in the heart helps prevent muscle rupture (as in skeletal muscle), but it also prevents overstretching of the heart. Length-tension analysis of cardiac muscle, for example, shows a dramatic increase in passive tension as cardiac muscle is stretched beyond its resting length. Skeletal muscle, in contrast, tolerates a much greater degree of stretch before passive tension increases to a comparable level. The reason for this difference between cardiac and skeletal muscle is not known, although one possibility is that stretch of skeletal muscle is typically limited by the range of motion of the joint, which in turn is limited by the ligaments/connective tissue surrounding the joint.

The heart, on the other hand, appears to rely on the abundance of connective tissue around cardiac muscle cells to prevent overstretching during periods of increased venous return. During intense exercise, for example, venous return may increase fivefold. However, the heart is capable of pumping this extra volume of blood into the arterial system with only minor changes in the ventricular volume of the heart (i.e., end-diastolic volume increases less than 20%). Although the abundance of connective tissue in the heart limits stretch of the heart during these periods of increased venous return, additional regulatory mechanisms help the heart pump the extra blood that it receives (as discussed in the section “Stretch”). Conversely, if the heart were to be overstretched, the contractile ability of cardiac muscle cells would be expected to decrease (because of decreased overlap of the thick and thin filaments), which would result in insufficient pumping, increased venous pressure, and perhaps pulmonary edema.

Within cardiac muscle cells, myofibrils are surrounded by the sarcoplasmic reticulum (SR) , an internal network of membranes (see Fig. 13.1B ). This is similar to the SR in skeletal muscle except that the SR in the heart is less dense and not as well developed. Terminal regions of the SR abut the T tubule or lie just below the sarcolemma (or both) and play a key role in the elevation of intracellular Ca ⁺⁺ during an action potential. The mechanism by which an action potential initiates release of Ca ⁺⁺ in the heart differs significantly from that in skeletal muscle (as discussed in the section “Excitation-Contraction Coupling”).

The heart contains an abundance of mitochondria; up to 30% of the volume of the heart is occupied by these organelles. The high density of mitochondria provides the heart with great oxidative capacity, more so than is typical in skeletal muscle.

The sarcolemma of cardiac muscle contains invaginations (T tubules) comparable to those seen in skeletal muscle. In cardiac muscle, however, T tubules are positioned at the Z lines, whereas in mammalian skeletal muscle, T tubules are positioned at the ends of the I bands. In cardiac muscle, the connections between the T tubules and the SR are fewer than, and not as well developed as, those in skeletal muscle. These junctional regions between the terminal portions of the SR and the T tubules in cardiac muscle are called dyads (as the junction consists of the T tubule membrane and one SR membrane), which contrasts with the triads in skeletal muscle where the T tubules are located between two SR terminal cisternae.

Control of Cardiac Muscle Activity

Cardiac muscle is an involuntary muscle with an intrinsic pacemaker. The pacemaker represents a specialized cell (located in the sinoatrial node of the right atrium) that is able to undergo spontaneous depolarization and generate action potentials. Of importance is that although several cells in the heart are able to depolarize spontaneously, the fastest spontaneous depolarizations occur in cells in the sinoatrial node. Moreover, once a given cell spontaneously depolarizes and fires an action potential, this action potential is then propagated throughout the heart (by specialized conduction pathways and cell-to-cell contact). Thus depolarization from only one cell is needed to initiate a wave of contraction in the heart (i.e., a heartbeat). The mechanisms underlying this spontaneous depolarization are discussed in depth in Chapter 16 .

Once an action potential is initiated in the sinoatrial node, it is propagated between atrial cells via gap junctions, as well as through specialized conduction fibers in the atria. The action potential can pass throughout the atria within approximately 70 msec. For the action potential to reach the ventricles, it must pass through the atrioventricular node, after which the action potential passes throughout the ventricle via specialized conduction pathways (the bundle of His and the Purkinje system ) and gap junctions in the intercalated disks of adjacent cardiac myocytes. The action potential can pass through the entire heart within 220 msec after initiation in the sinoatrial node. Because contraction of a cardiac muscle cell typically lasts 300 msec, this rapid conduction promotes nearly synchronous contraction of heart muscle cells. This is a very different scenario from that of skeletal muscle, in which cells are grouped into motor units that are recruited independently as the force of contraction is increased.

Excitation-Contraction Coupling

Blood and extracellular fluids typically contain 1 to 2 mmol/L of free Ca ⁺⁺ , and it has been known since the days of the physiologist Sidney Ringer (ca. 1882) that the heart requires extracellular Ca ⁺⁺ to contract. Thus an isolated heart typically continues to beat when perfused with a warm (37°C), oxygenated, physiological salt solution that contains approximately 2 mmol/L Ca ⁺⁺ (e.g., Tyrode’s solution), but it stops beating in the absence of extracellular Ca ⁺⁺ . This cessation of contractions in Ca ⁺⁺ -deficient media is also observed in hearts that are electrically stimulated, which further demonstrates the importance of extracellular Ca ⁺⁺ for contraction of cardiac muscle. This situation is quite different from that of skeletal muscle, which can contract in the total absence of extracellular Ca ⁺⁺ .

Action potentials in cardiac muscle are prolonged, lasting 150 to 300 msec ( Fig. 13.2 , inset ), which is substantially longer than the action potentials in skeletal muscle (≈5 msec). The long duration of the action potential in cardiac muscle is due to a slow inward Ca ⁺⁺ current through an L-type voltage-gated calcium channel in the sarcolemma. The amount of Ca ⁺⁺ coming into the cardiac muscle cell is relatively small and serves as a trigger for release of Ca ⁺⁺ from the SR. In the absence of extracellular Ca ⁺⁺ , an action potential can still be initiated in cardiac muscle, although it is considerably shorter in duration and unable to initiate a contraction. Thus, influx of Ca ⁺⁺ during the action potential is crucial for triggering release of Ca ⁺⁺ from the SR and thus initiating contraction.

The L-type voltage-gated calcium channel is composed of five subunits (α ₁ , α ₂ , β, γ, and δ). The α ₁ subunit in cardiac muscle is also called Ca _V 1,2. Historically, Ca _V 1.2 was called the dihydropyridine receptor (DHPR) because it binds the dihydropyridine class of L-type voltage-gated calcium channel–blocking drugs (e.g., nitrendipine and nimodipine). Note that cardiac muscle contains Ca _V 1.2, whereas skeletal muscle contains Ca _V 1.1, which is very important, as it changes the mechanism by which an action potential in the T Tubule induces Ca ⁺⁺ release from the nearby SR (as discussed later).

In each cardiac muscle sarcomere, terminal regions of the SR abut T tubules and the sarcolemma (see Figs. 13.1B and 13.2 ). These junctional regions of the SR are enriched in calcium release channels called ryanodine receptors (RYR). The RYR2 isoform is the Ca ⁺⁺ -gated calcium release channel in cardiac SR. A critical point to appreciate is that during an action potential in the myocardial cell, the tiny amount of Ca ⁺⁺ passing through the L-type Ca ⁺⁺ channel in the T tubule stimulates the nearby RYR2 to release Ca ⁺⁺ from the terminal cisterna into the cytoplasm. The Ca release from the SR then promotes actin-myosin interaction, and hence contraction.

The amount of Ca ⁺⁺ released into the cytosol from the SR is much greater than that entering the cytosol from the T tubule or sarcolemma, although release of Ca ⁺⁺ from the SR does not occur without this entry of “trigger” Ca ⁺⁺ . Thus excitation-contraction coupling in cardiac muscle is termed electrochemical coupling (with voltage-induced Ca ⁺⁺ influx through Ca _V 1.2 stimulating Ca ⁺⁺ release from RYR2), whereas excitation-contraction coupling in skeletal muscle is termed electromechanical coupling (with a voltage-induced conformational change in Ca _V 1.1 promoting Ca ⁺⁺ release from RYR1 through protein-protein interactions). The basis for this difference in Ca ⁺⁺ release mechanisms appears to depend on the differences between Ca _V 1.1 in skeletal muscle and Ca _V 1.2 in the heart.