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Figure 14-1. Two arrangements of musclefibers within a muscle. A. Parallelarrangement: Tendons are lines radiatingfrom rectangles (muscle fibers) at each end.B. Pennate arrangement: Tendons arevertical lines extending from the two sidesof the parallelogram. Double headedarrows (f) indicate direction of forceexerted by individual muscle fibers;single-headed arrows (F) indicate directionof force exerted by whole muscle. (ZierlerKL: Mechansims of muscle contraction andits energetics. In: Mountcastle VB [ed]:Medical Physiology. 13th ed, Vol. 1. St.Louis, C.V. Mosby, 1974).

CHAPTER 14

MUSCLE CONTRACTION

It is impossible to overemphasize theimportance of muscle in vertebrates. The very life style of every one demands

movement, impossible without muscle. Infact, in man about 40% of the body mass isstriated muscle, making it the most abundanttissue. Striated muscle is so namedbecause of its characteristic cross-stripedappearance. Most striated muscle is skeletalmuscle, involved in rotation of bones aroundjoints and therefore responsible for most ofthe movements of which we are aware. Other striated muscles move the eyes andserve as valves to check the flow of blood orother fluids, e.g., the bulbospongiosus aidserection of the penis or clitoris bycompressing the deep dorsal vein. Cardiacmuscle is also striated in appearance, but itdiffers significantly from other striatedmuscle in both its structure and its behavior. Still other muscles, called smooth muscles,lack the characteristic cross-striations, butcontain the same contractile proteins. Thesmooth muscles are important as linings ofthe gastrointestinal tract that churn andpropel food through the tract, as linings ofblood vessels that control their diametersand thus flow through them, as valves thatcontrol the passage of gases and fluids in thebody, and as controllers at many other placesin the body.

Of the three types of muscle, skeletal andcardiac muscle have been studied mostthoroughly. It is presumed that themechanism of contraction is the same forboth types and only the details of initiatingand controlling the contraction differ. Notall striated muscle, however, behaves in the

same way. For example, skeletal muscles ofvertebrates all appear to initiate contractionswith sodium spikes, whereas striatedmuscles of some invertebrates initiatecontractions with calcium spikes. We willconfine our discussion primarily tovertebrate skeletal muscle, pointing out thedistinctive features of structure and functionof cardiac and smooth muscle.

Muscle structure.Skeletal muscles are composed of masses

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of fibers, each an individual cell. There areseveral types of muscles, each with differentarrangements of fibers, but these can bedivided into two major classes: those withfibers arranged in parallel and those with apennate arrangement. Figure 14-1 showsthese two classes. In the parallelarrangement (A), each muscle fiber, or asmall group of fibers, is attached to its owntendon, the tendons converging on acommon point1. The muscle fibers are side-by-side, i.e., in parallel, but the name of theclass comes from the fact that the musclefibers shorten in a direction (double headedarrow, f) parallel to the direction ofshortening of the muscle (single-headedarrow, F).

The pennate muscle fibers (B) attach to acommon tendon, so that the direction ofshortening of the individual fibers (double-headed arrow, f) is different from thedirection of shortening of the whole muscle(single-headed arrow, F). As a result, thepennate muscle cannot shorten as much asthe parallel muscle. Pennate muscles arelocated in positions requiring small butpowerful movements; parallel muscles arelocated in positions requiring longermovements with less power or fastermovements.

1 In Fig. 14-1, muscle fibers arerectangles or parallelograms, tendons arelines radiating from the muscle fibers orvertical lines extending from the two sidesof muscle fibers, arrows labeled f indicatedirection of force exerted by fibers, andarrows labeled F indicate direction of forceexerted by the whole muscle.

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Figure 14-2 - Levels of organization within a skeletal muscle, including (counterclockwise from top left) whole muscle andfascicles, bundles of muscle fibers, myofibrils, thin and thick filaments, and myosin and actin molecules. (Warwick R, WilliamsPL [ed]: Grays' Anatomy. 35th British ed, Edinburgh, Churchill Livingston, 1973; modified from a drawing by Professor DFawcett)

Muscles, fibrils and filaments. Tounderstand how a muscle works it isnecessary to understand the fine-structure ofmuscle cells because it is the internal partsof the cells that do the work. The relevantinternal structures are the myofibrils, themyofilaments and the sarcoplasmicreticulum. Muscles are composed of musclefibers; fibers are composed (in part) ofmyofibrils; and myofibrils are composed ofmyofilaments. Skeletal muscles have acharacteristic striated appearance becausethe myofibrils are characteristically striatedand because the myofibrils are more or less

in register (the same stripes are lined up). The myofibrils are striated because themyofilaments are not homogeneouslydistributed within them, but rather occur inregular, repeating arrays.Myofibrils. Figure 14-2 shows, on the left,

the whole muscle, a bundle of muscle fibers,and their subunits, the myofibrils. Note thestriated appearance of all three. Eachmuscle fiber contains about 1000 myofibrilsthat are 1 :m in diameter and run the lengthof the fiber. Myofibrils have no membrane,being simply surrounded with cytoplasm.The cross-striations of the myofibrils are

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Figure 14-3. Organization of the sarcomeres. A. Pattern ofcross-striation in skeletal muscle with bands labeled. B.Arrangement of thick and thin filaments that accounts for thepattern of cross-striations. C. Hexagonal arrays of thick andthin filaments in cross sections through the sarcomere in theA band, H band and I band.

serially repeating units called sarcomeres. A sarcomere can be from 1.5-3.5 :m inlength, depending upon the contractile stateof the muscle, and it is bounded on each endby a disc, called the Z disc or Z line. Eachsarcomere contains an anisotropic (doublyrefractive, therefore dark in phase micro-scopy) band bounded by two isotropic(singly refractive, therefore light) bands. The anisotropic band is called the A band;the isotropic band is called the I band. Actually, each sarcomere contains two half-Ibands (one at each end) because a single Iband straddles the Z line and therefore ispart of two adjacent sarcomeres. In thecenter of the A band, there is a lighter regionknown as the H zone or H band. Duringcontraction the A band does not changelength2, though the sarcomere shortens, thedistance between Z lines lessens, and the Iand H bands narrow. Any theory of musclecontraction must account for theseobservations.

The myofibrils, as shown in Figure 14-2,are composed of proteinaceous structurescalled myofilaments. One filament is thick,about 11 nm in diameter and 1.5 :m long,whereas the other is thin, 5 nm in diameterand 1 :m long. These filaments are referredto as the thick filaments and thinfilaments, respectively. Thick filaments aremade up of several hundred myosinmolecules, proteins of a molecular weight ofabout 500,000, and some other minorproteins whose function is unknown. Themyosin molecule has a tail region that isrodlike, and head region, with two globular

subunits projecting out at approximatelyright angles with the filament. The structurehas been likened to two golf clubs with theirshafts twisted together. Drawings of amyosin molecule, and its position within thethick filaments are shown in Figure 14-2. The myosin molecules of thick filaments arearranged in a sheaf with heads orientedtoward each end and tails toward the center. Each subsequent myosin molecule attaches14 nm further toward the end of thefilament, and its head is rotated 60° aroundthe filament from its predecessor. Thus, thethick filament is studded with projectionsexcept at its center, which contains onlymyosin tails. Note that myosin molecules atopposite ends of the thick filament areoriented in opposite directions–sort of like abundle of unsorted golf clubs, some withheads at the right end, some with heads onthe left. The thick filaments are coincidentwith the A band of the sarcomere.

2 Actually, it is generally accepted that inLimulus, the horseshoe crab, the A bands dochange length when contractions occur atlengths less than the resting length. Theyapparently do not in mammalian muscle.

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Figure 14-4. Thin filament structure. Proposed structure of thinfilament with relative positions of actin, troponin andtropomyosin indicated. (Ebashi S, Endo M, Ohtsuki I: QuartRev Biophys 2:351-384, 1969)

Troponin and tropomyosin are regulatoryproteins that allow the muscle to shortenin the presence of Ca++.

Each thin filament contains three proteinmolecules: actin, troponin, andtropomyosin. A single thin filament iscomposed of 300 to 400 actin molecules and40 to 60 troponin and tropomyosinmolecules. Actin is a small, nearly sphericalmolecule that is arranged in the filament intotwo helical strands, as shown in Figure 14-2,with about 13 actin molecules per completeturn of the helix. Troponin and tropomyosinare sometimes called regulator proteinsbecause of their central role in regulatingmuscle contraction. Tropomyosin is afilamentous protein that is thought to formtwo strands that lie in the grooves formedbetween the actin strands. Troponin, aglobular protein, binds to tropomyosin atonly one site and therefore is thought to sitastride the tropomyosin molecule strand atregular intervals approximating 40 nm. Figure 14-4 shows the relationships betweenthe three proteins as they are currentlythought to exist. The thin filaments attach tothe Z disc, a flat protein structure. Thinfilaments may be connected end-to-end inthe H band by slender threadlike processes.

The relatively high anisotropicity of theA band results from the presence of boththin and thick filaments (shown inlongitudinal section in the upper part andcross-section in the lower part of Fig. 14-3). The I band is only slightly anisotropicbecause it contains only thin filaments. TheH band is not optically as dense as the rest ofthe A band because it does not contain anythin filaments when the muscle is at rest. Ascan be seen in the cross section of Figure 14-

3, the thin filaments are organized intoregular hexagonal arrays within themyofibrils, with a thick filament at thecenter of each array in the A band. Threethick filaments are equidistant from eachthin filament, whereas six thin filaments areequidistant from each thick filament asshown in the left panel. A cross sectionthrough the I band shows only the thinfilament array; a section through the H bandshows only the thick filament array (plus theslender, thread-like processesinterconnection thin filaments).

The myosin heads project out from thethick filaments toward the thin filaments atintervals of about 43 nm measured in a lineparallel to an adjacent thin filament. Because they are staggered around the thinfilament at 60° intervals, each projects in thedirection of a thin filament, and each thinfilament has projections toward it from threethick filaments. These projections havebeen termed either cross-bridges or cross-projections, depending upon whether theheads are thought to contact and bind thinfilaments or not. As we shall see, there aretwo schools of thought, in fact, two differentmechanisms proposed to account for thegeneration of the mechanical force ofcontraction.

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Figure 14-5. Three-dimensional reconstruction of skeletalmuscle illustrating organization of myofibrils, sarcoplasmicreticulum and T tubules. (Warwick R, Williams PL [ed]:Gray's Anatomy, 35th British ed, Philadelphia, W.B.Saunders, 1973)

Figure 14-6. Fortuitous sections through triads, one at rightangles to the other. Relative positions of T tubules andsarcoplasmic reticula at the triad are shown clearly.

Muscle cells have a unique membranestructure, called the transverse tubule orsimply the T tubule. The T tubule is aninvagination of the muscle membrane, muchlike the invagination produced in a balloonby pushing a finger into its side withoutpuncturing it, but the T tubules are long andtortuous. The T tubule system forms a ringaround every myofibril either at the Z line,in which case there is one per sarcomere, orat the A-I-band junction, in which case thereare two per sarcomere. These perifibrillarrings are inter-connected, forming a kind ofhoneycomb arrangement, as shown in Figure14-5. The position of the T tubule withrespect to the sarcomere is somewhatspecies specific; frog skeletal muscle hasonly one tubule per sarcomere, whereashuman skeletal muscle has two. It should benoted that in human cardiac muscle there isonly one tubule per sarcomere as shown in

Figure 14-22. The inside of the T tubule iscontinuous with the extracellular space andpresumably contains a fluid likeextracellular fluid, but, because the tubularspace is small and not well stirred, it islikely that ionic movements across thetubule membrane produce significantchanges in ionic concentration, at least on ashort-term basis.Another intracellular structure with special

significance for contraction is thesarcoplasmic reticulum, the muscle cellversion of the endoplasmic reticulum. Thesarcoplasmic reticulum is made up oftubules that run parallel to the sarcomeresfrom T tubule to T tubule (see Figures 14-5and 14-19); thus, there are two sets ofsarcoplasmic reticulum tubules persarcomere in muscles with two sets of Ttubules per sarcomere. The sarcoplasmicreticulum is a sack with its ends expanded(the cisternae) adjacent to the T tubules andwith narrow, longitudinal channels

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Figure 14-7. A model of the opening of the Ca channel by the action potential is the Ttubule of the skeletal muscle fiber.

connecting theseexpansions, one at each end. In fortuitous sections, onecan find a section of T -tubule bounded on twosides by sort of dumb-bell-shaped sarcoplasmicreticula as illustrated inFigure 14-6. The T tubulewith its two adjacentregions of sarcoplasmicreticulum is often called atriad. Because the T tubulesand the cisternae of thesarcoplasmic reticulum runtogether for such a long way, a largeproportion of the sarcoplasmic reticulum isin contact with the sarcolemma. There is aspace of about 12 nm between themembranes which, in electron micrographs,appears to be traversed at regular intervalsby structures that have been suggested to bechannels coupling the T tubule with thesarcoplasmic reticulum. However, largemolecules such as ferritin cannot crossbetween the two structures, and the lumen ofthe sarcoplasmic reticulum contains a fluidlike sarcoplasm, not like extracellular fluid. In addition, electrical measurements indicatethat the sarcoplasmic reticulum does notcommunicate with the T tubule through lowresistance pathways.

One model has a mechanical plug thatcloses the Ca channel, preventing calciumfrom leaving the sarcoplasmic reticulum.Hypopolarization of the T tubule somehowpulls the plug out of the channel opening,allowing Ca to enter the sarcoplasm. InFigure 14-7, the plug is show in red (ladle-shaped piece) and the Ca channel in purple(cut cylinder). Presumably, the plug is adipole whose position is altered by alteringthe membrane polarization. In any case, Ca

efflux from the sarcoplasmic reticulum startsthe muscle contraction.The sarcoplasmic reticulum serves as a

repository for Ca++. In rested muscle, Ca++ isfound in high concentration in the cisternaeat the triad. In recently active muscle, thecalcium is found in the narrowed,longitudinal portion from which it moves tothe triad as time passes. During contraction,Ca++ is found in high concentration outsidethe sarcoplasmic reticulum among themyofilaments.

Sliding filament modelObservations that during muscle

contraction, the sarcomere, the I and Hbands become narrower, while the A banddoes not, coupled with the observation thatthick and thin filaments do not shorten(although at very short lengths the thinfilaments may either push through the Z lineor fold up like an accordion), suggested thesliding filament model of contraction. According to the model, the thick and thinfilaments simply slide past each other.

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Figure 14-8. Slidingfilament model ofmuscle contraction. Asingle sarcomere isshown stretched, withlittle overlap betweenthick and thin filaments(A), with greater overlap(B), with completeoverlap (C), andextremely shortenedwith thin filamentsshown buckled (D).Another possibility, notshown, is that at extremeshortening, the bucklingoccurs at the Z line.

According to the sliding filamenthypothesis, thick and thin filamentssimply slide past each other to produceshortening.

Figure 14-9. The skeletal muscle action potential. Thespike is followed by a depolarizing tail that lasts 4 to 5msec.

Figure 14-8 showsseveral positions in theshortening of themuscle, illustrating thesliding of the filaments. At the maximum lengththere is little or nooverlap of the filaments(A), but as the muscleshortens there is moreand more overlap untilthe fibers completelyoverlap (D). There isgeneral agreement thatthe sliding filamentmodel is an accuratedescription of whathappens during musclecontraction.

Events leading to contractionAlthough muscle contraction can be

initiated by direct electrical stimulation ofthe muscle, it usually results from activity inthe motoneurons innervating the muscle. Anaction potential initiated in an "-motoneuronpropagates into the motoneuron terminalsand releases acetylcholine into the synapticcleft. The acetylcholine induces an end-plate potential in the muscle which, innormal muscle, always leads to an action

potential in the muscle. The muscle spike isvery much like the nerve spike but longer induration and with a hypopolarizing tail onthe falling phase that prolongs the spike by3-4 msec. An example of a muscle spike isshown in Figure 14-9. The mechanism ofgeneration of the spike in mammalianstriated muscle is the same as that describedfor nerve in Chapter 3. The long (4-5 msec)hypopolarizing tail of the muscle actionpotential is probably the electrotonicreflection of the action potential as itconducts into the T tubules. At least, the taildisappears from the spike when the muscleis treated with glycerol and then returned toRinger's solution, a treatment that more orless specifically ruptures T tubules, leavingthe surface membrane and resting potentialintact. The muscle still generates a spike butdoes not contract. Conduction of the spikeinto the T tubules is probably an activeprocess as elsewhere on the membrane, andit is the hypopolarization of the T tubule thatleads to contraction.It is reasonable to ask why there exists such

an elaborate system of tubules in striatedmuscle. The answer may lie in thesynchronization of contraction of sarcomeres

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Figure 14-10. Production of force according to the cross-bridge theory. Cross-bridges, projecting from the thick filament, areshown attached to the thin filament and swiveled (dashed outline). Directions of force and translation are indicated by arrows.(Nobel MIM, Pollack GH: Circ Res 40:33-342, 1977)

along the length of the muscle and in itsdepths. The myofibrils are locatedthroughout the muscle fiber, but inmammalian muscle there is usually only oneneuromuscular junction per fiber. If therewere no way for the hypopolarization of thespike to get into the center of the fiber, themyofibrils on the surface would contractbefore those in the center. With the T-tubulesystem, the spike is conducted rapidly to allparts of the cell, reaching all of themyofibrils at nearly the same time. In theabsence of such a mechanism, contractingsegments of the myofibrils would stretch thenon-contracting ones, lessening the forcetransmitted to the ends of the fibers and,therefore, to the joints.

The hypopolarization of the T tubulesopens special voltage-gated channels inopposing regions of the sarcoplasmic

reticulum membrane. By an as yetincompletely understood mechanism, thisleads to a release of calcium from thecisternae of the sarcoplasmic reticulum intothe region of the myofilaments. This is anessential step in the contraction mechanism;muscles depleted of calcium do not contract. The calcium diffuses to the thin filamentsand binds to troponin. Each head of themyosin molecule (a molecule has two) is anATPase, capable of hydrolyzing ATP toADP and inorganic phosphate, releasingenergy; however, according to currentthought, tropomyosin inhibits the ATPase. The combination of troponin with Ca++

removes the tropomyosin inhibition, perhapsby inducing a conformational change in thethin filament.

Cross-bridge theory.To this point, most theories of

contraction agree. There are, however, twoplausible theories of how the force ofcontraction develops. The first, the cross-

bridge theory, suggests that an actualphysical binding of the myosin head to thethin filament occurs, that the hydrolysis ofATP causes a rotation of the head toward thetail, pulling on the compliant arm of the

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The cross-bridge theory says that slidingis produced by physical attachment ofmyosin heads to actin and by rotation ofthe heads.

cross-bridge. This pull results in a relativemovement of thin and thick filaments andtension and shortening of the sarcomere. Indetail, ATP binds to myosin and then, in thepresence of Ca++, troponin, and tropomyosin,a myosin binding site is exposed on the thinfilament and a physical link is formedbetween actin and myosin. The ATPaseactivity of the myosin is then exerted,cleaving a phosphate bond of the ATP,releasing energy, and causing the myosinhead to swivel. Figure 14-10 shows the wayin which the myosin head is thought torotate (solid and dashed outlines of myosinheads are meant to indicate two differentpositions of the heads as they rotate) and therelative movement of the filaments thatresults. Because the heads of the myosinmolecules are oriented in opposite directionsat opposite ends of the thick filament, eachpulls its adjacent thin filament toward thecenter of the sarcomere and the sarcomereshortens.

When the hypopolarizing stimulus of thespike in the T tubules is over, calcium ceasesto be released by the cisternae of thesarcoplasmic reticulum and actively pumpedinto the longitudinal portion of thereticulum. The Ca++ pump that pumps Ca++

from the cytosol back into the sarcoplasmicreticulum is an ATPase that is phosporylatedand dephosphorylated during the pumpingprocess. It pumps two Ca++ ions for eachATP hydrolyzed. In muscle, the Ca++

ATPase accounts for nearly 90% of themembrane protein and therefore is capableof pumping Ca++ ions rapidly. Typically, thecytosolic Ca++ concentration is restored toresting levels within 30 milliseconds. Whencalcium is removed from the myofibrils,ATP replaces ADP on the myosin complexand the myosin-actin bond is broken. Because the muscle is elastic, it will be

restored to its resting length in the absenceof a further stimulus to release calcium. Shortening is an active process; lengtheningis a passive process.

A single cycle of attachment, swivel, anddetachment of the myosin head will producea linear translation of the myofilaments ofabout 10 nm. If all cross-bridges in amyofibril cycle once synchronously, arelative movement equal to about 1% of themuscle length will occur, but obviouslymuscles shorten by more than 1%. The totalshortening of a sarcomere during contractionmay exceed 1,000 nm; therefore the relativemovement of a thin and thick filamentwould be half this amount or 500 nm. Toachieve this magnitude of change in totallength when each cross-bridge cycleproduces a 10-nm shortening, a minimum of50 cycles must occur. The flexor muscles ofthe human upper arm can contract at the rateof 8 m/sec (Wilkie DR: J Physiol (Lond)110:249-280, 1949), during which they canshorten by as much as 10 cm. Thiscontraction rate gives a contraction rate forthe sarcomere of 160 nm/msec. If a strokeof the cross-bridge is taken to be 10 nm,then at this rate there will be a minimum of16 strokes/msec. Thus, the swivel time forthe cross-bridge must be of the order of 60:sec. Calculations for the frog's sartoriusmuscle, which can shorten at up to 4 cm/sec,indicate a swivel time of about 1 msec, butthis contraction occurs at a lowertemperature than those in mammals. In anycase, it is clear that the swiveling of the

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cross-bridge must be a fast mechanicalprocess.

The cross-bridge theory assumes that theforce generated by the muscle isproportional to the number of cross-bridgelinkages formed at that time and that theprobability of formation of a cross-bridge isproportional to the speed of shortening, i.e.,the probability is great when attachmentsites move slowly past one another, smallwhen they move rapidly. If tension is afunction only of the number of cross-bridges, then there should be a linearrelationship between length and tension suchthat tension increases with decreasing length

because of the greater overlap of thick andthin filaments at shorter lengths. The forcerequired to stretch the muscle at any time istherefore also proportional to the number ofcross-bridges–it is the force required tobreak the actin-myosin bonds.In summary, l) tension is developed by

physical bonds between thick and thinfilaments, 2) tension depends upon thedegree of overlap between thick and thinfilaments, 3) the cross-bridge originates atthe thick filament and terminates at the thinfilament.

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Table 14-1

Summary of Events in Muscle Contraction and Relaxation

Arrival of motoneuron action potential9

Synaptic transmission at neuromuscular junction9

Action potential propagates along sarcolemma9

Hypopolarization of T tubules9

Ca++ released into sarcoplasm from sarcoplasmic reticulum9

Ca++ bound by troponin9

Cooperative configurational change in troponin and tropomyosin9

Release of inhibition of myosin-ATPase9

Link between thick and thin filaments,swivel of myosin head

9Tension exerted

9Shortening by sliding filament

9Ca++ removed from sarcoplasm

Mg++ATP bound by actinomyosin9

Cross-bridges disconnected9

Actinomyosin-ATPase inhibited9

Active tension disappears9

Series elastic elements restore resting length

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Figure 14-11. Series and parallel elastic elements inmuscle. A. Resting muscle contains elastic elements inseries with the contractile elements (sarcomeres) and inparallel with them. B. During an isometric contraction, themuscle does not change length, but sarcomeres shorten,stretching the series elastic elements. C. During isotoniccontraction, the contractile elements shorten, stretching theseries elastic elelments, before they develop tension to liftthe load. D. Muscle begins to shorten when contractileelements shorten further.

Figure 14-12. Relation between muscle actonpotential and twitch contraction. The time course ofthe action potential is indicated in A and the longerdevelopment of tension (ordinate) of the twitchcontraction is shown in B. (Dudel J: Muscles. InSchmidt RF [ed]: Fundamentals ofNeurophysiology, 2nd ed. New York,Springer-Verlag, 1978)

Properties of contracting muscle.When a muscle is stimulated either

directly or synaptically, it develops tensionand, if allowed to, it contracts, i.e., itshortens3. In this section we will discuss theways in which a muscle contracts.

Isometric versus isotonic contraction. When a muscle is stimulated after its ends ortendons have been fixed, it contracts butcannot shorten. This is called an isometriccontraction (iso = same, metric =measurement or length). The muscledevelops tension, but because it does notshorten, it does no external work (recall:work = force x distance moved). Carefulobservation reveals that during an isometriccontraction some sarcomeres of the muscleshorten, stretching other sarcomeres and, inaddition, stretching elastic elements of themuscle, increasing the tension measured atthe tendon. Figure 14-11A is a schematicdiagram of the muscle, showing elasticelements both in series and in parallel with

the contractile elements (the myofibrils) ofthe muscle. When a whole resting muscle ora single resting muscle fiber is stretched, it opposes the stretch witha force that increases with increased stretch(like a rubber band). This elasticity is due tothe parallel elastic elements that lie, for themost part, outside the contractile elements inelastic tissues, including tendons and thesarcolemma. (When the muscle contracts,the shortening of the muscle lags behind theshortening of the sarcomeres because of theseries elastic elements.) Therefore, in theisometric contraction, the sarcomeresshorten and stretch the series elasticcomponent even though the muscle as awhole does not shorten, as shown in Figure14-11B. Even though there is no externalwork being done by the muscle, there isinternal work being done.If only one end of the muscle is fixed, the

muscle shortens and, if it shortens with aconstant load, the contraction is isotonic (iso= same, tonic = tension). When the

3 An active muscle always developstension but does not always shorten.

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A single action potential produces atwitch contraction. Multiple contrac-tions may sum.

Figure 14-14. Set up for length-tension experiments. Themuscle is indicated by an ellipse with two tendons at eitherend of the long axis. A strain gauge has been introducedinto one tendon to measure tension. The nerve to themuscle is indicated as is the pulse applied to initiate atwitch contraction. The middle drawing is meant to indicateresting length, the upper some length less than resting, andthe lower some length less than resting. At the right of eachdrawing is the twitch contraction initiated in each case.

contractile elements shorten they must firststretch the series elastic elements anddevelop a tension equal to the load beforethe next increment in tension causes the loadto be lifted. All of the contraction thatoccurs before the load is lifted is isometric. Even if the muscle carries no external load,it still must develop a tension equal to itsown weight before it can shorten. Whencontractile forces exceed the load,shortening begins; tension remains slightlylarger than the load throughout shortening. Shortening stops when active tension dropsto the point where it equals the load. At thispoint, contraction again becomes isometric. The muscle lengthens (is stretched) whenthe total tension in the muscle falls belowthe load. Figure 14-11C and D show thechanges in both series and parallel elasticelements and in the contractile elementsduring an isotonic contraction. In C, thecontractile elements have shortened,stretching the series elastic elements, but themuscle has not shortened. In D, the furthershortening of the contractile element leads toshortening of the muscle because the serieselastic elements are already stretched.

Twitch and tetanic contractions. If abrief stimulus is applied to the muscle or asingle stimulus is applied to the nerve, asingle action potential will be elicited in themuscle and, after an activation delay ofabout 5 msec, the muscle will contract. Thetime-course of this contraction, called atwitch contraction, is shown in Figure 14-12B. The tension in the muscle rises rapidlyto a maximum, about 50-80 msec after thestimulus and then returns to resting tensionover the next 100-200 msec or so, dependingupon the particular muscle. In A, the muscleaction potential is reproduced forcomparison with the twitch, which lastsabout 100 times longer. The muscle whose

contraction is shown in the figure, theadductor pollicis muscle of the thumb, is afast muscle. As we shall see, mammals alsohave slow muscles that require 200 msec ormore to attain their maximum twitchtension.

A second stimulus, applied before themuscle has completely relaxed, inducesanother contraction that adds to the first, thesum of the tensions being greater than thatof a single twitch. This event, as youprobably have guessed, is calledsummation. An example is shown inFigure 14-13. A single stimulus evokes thetwitch at the left in A. Repeated stimulation

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Skeletal muscles produce themaximum force when they contractfrom the resting length.

Figure 14-15. Length-tension curve. Isometric tension (ordinate) isplotted against muscle length (abscissa) expressed as a fraction ofresting muscle length, 1.0. The muscle's elasticity resists stretch,causing tension that follows the dotted curve; this is passive tension.When the muscle's length is fixed at a value on the abscissa and thenit is stimulated to contract, it develops tension that lies on the dashedcurve. This is the total tension or the sum of passive tension anddeveloped tension. The difference (solid curve) between the dashedand dotted curves is the tension developed by the muscle when itcontracts. This is maximum at the resting length. (Dudel J: Muscles.In Schmidt RF [ed]: Fundamentals of Neurophysiology, 2nd ed. NewYork, Springer-Verlag, 1978)

at a rate of 10/sec evokes the summedtensions in B. When the stimulusfrequency is increased to 50/sec, thetension rises to a more-or-less steadyvalue, much greater than the twitchtension. This summation, as in C, is calledtetanus or tetanic contraction. Becauseindividual twitch contributions to thetetanus can still be seen as bumps in therecord, this tetanus is called unfused orincomplete. At even higher rates ofstimulation, the maximum tension themuscle can sustain is obtained and there isno sign of individual twitches in therecord. This is called fused or completetetanus, and it is shown in Figure 14-13Dfor a 100/sec stimulation rate. Fast andslow muscles, as defined by their twitchtimes, also differ in the least stimulusfrequency at which their contractionsproduce fused tetanus. Fast muscles maynot fuse until stimulus rates equal orexceed 60/sec, whereas slow muscles mayfuse at rates of only 16/sec.

Length-tension relation. When aresting skeletal muscle is stretched fromits resting length, i.e., its length at rest in thebody, the parallel elastic elements arestretched and tension increases along theblue curve (A) in Figure 14-15. In thisfigure, length, expressed as a fraction ofresting length, is plotted on the abscissaagainst tension (or force) on the ordinate. Ifthe muscle is stretched to about 180% of itsresting length (this is about the maximumstretch without damage to the muscle), andthe length is held constant at this value whilea contraction is induced (the set up for thisexperiment is shown in Figure 14-14), themaximum isometric tension of the muscle isobtained. This tension (total tension) is thesum of the parallel elastic tension (i.e.,passive tension) and the contractile tension

(i.e., active tension). At any length less than180% of the resting length, the total tensiondeveloped by the muscle during an isometriccontraction will be less and will follow thered curve (B) in Figure 14-15. To computethe contractile tension, the tensiondeveloped by the contractile elements, wesimply subtract the blue curve (A) from thered curve (B). The result is the dotted curve,sometimes referred to as an isometriclength-tension curve.Obviously, the maximum isometric

contractile tension occurs when the muscle

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Figure 14-16. Force-velocity curve. Velocity ofshortening (ordinate) is plotted against the load (force)applied to the muscle (abscissa). As the load increases, thevelocity of shortening decreases. The curve isextrapolated back to zero load, yielding the maximumvelocity the muscle can achieve, Vmax. (Aidley DJ: ThePhysiology of Excitable Cells. Cambridge, CambridgeUniv Press, 1971)

is at its resting length. At shorter or longerlengths, the isometric tension produced bythe contractile elements is less. The exactshape of the curve for lengths longer thanthe resting length depends upon when andhow the tension is measured (for adiscussion see Noble MIM, Pollack GH:Molecular mechanisms of contraction. Circ

Res 40:333-342, 1977). At lengths less thanabout 70% of resting length, the muscledevelops no tension at all when stimulated. It follows that, during an isotoniccontraction, a skeletal muscle can onlyshorten to about 70% of its resting length,and it can only develop tension at lengthsbetween 70% and 180% of resting length. The isotonic length-tension curveapproximately superimposes upon theisometric curve; hence during an isotoniccontraction the muscle shortens to a lengthappropriate for the tension developed (i.e., to

a length predictable from the isometriclength-tension curve).The length-tension curve can be explained

by the cross-bridge theory. Instead of thelength of the whole muscle, we could just asaccurately have plotted sarcomere length onthe abscissa of Figure 14-15, with restinglength equal to about 2 :m. At restinglength, the thin and thick filaments are inrelative positions as shown in Figure 14-7C,with nearly the whole thick filamentoverlapped by thin filaments. In thisposition, all of the myosin heads areoverlapped by the thin filament, andtherefore all are available to form cross-bridges. Recall that in the cross-bridgetheory the force of contraction isproportional to the number of cross-bridgesformed. At longer lengths, such as those inA and B of Figure 14-7, some of the myosinheads are not overlapped by actin andtherefore are not available to form cross-bridges. As a consequence, the tensiondeveloped will be less. At shorter lengths,such as D, the actin filaments from oppositeends of the sarcomere begin to interfere witheach other and at shortest lengths the Z discmay block or otherwise impede movementof the thick filament.Force-velocity relation. Even though the

conditions are right for an isotoniccontraction, i.e., the muscle is fixed at onlyone end and a weight is attached to theother, the velocity of shortening will be zero(or negative, i.e., the muscle will lengthen)when the weight applied to the muscle ismore than the muscle can lift. On the otherhand, when there is no weight on themuscle, it will shorten at its maximumvelocity. These are the boundary conditionsof the force-velocity relation. Betweenthese two extremes, the velocity ofshortening decreases as the load increases.

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The smaller the load, the morerapid the contraction.

Figure 14-17. Force-velocity curve at different initiallengths. Because the force developed varies withinitial length, one would expect to find differentforce-velocity curves for different initial lengths.Two are shown in this figure.

Earlier measurements of the velocity ofshortening during isotonic contractionsindicated that the velocity was an hyperbolicfunction of the load4 being lifted, as shownin Figure 14-16. Newer measurementsindicate that this is not usually the case (HillAV: First and Last Experiments in MuscleMechanics. London, Cambridge UniversityPress, 1970). In both skeletal and cardiacmuscle, the relationship, measured at thesarcomere level, is clearly not hyperbolic. The exact shape of the curve is, however,less important for this discussion than thefact that velocity decreases with increasedload. Notice that the solid curve does notintersect the ordinate. This is because it isdifficult experimentally to make the loadzero in a practical way. (Under mostconditions, the muscle must lift at least itsown weight.) We can extrapolate the curveback to the ordinate to find out what thevelocity at zero load would be (dashed line,extending the curve in Figure 14-16). Thisis the maximum velocity or Vmax.

Actually, because the force exerted bythe muscle is also related to its length, therewill be a family of curves like that in Figure14-16. The curve shown was obtained whenthe muscle started to contract at its restinglength. The force generated at greater orlesser initial lengths will be less than that atthe resting length. Therefore, all of thecurves for lengths other than the restinglength will be roughly parallel to, but belowthat shown in Figure 14-16. They will beroughly parallel except near zero load, whereall the curves will converge onto the samevalue of Vmax (Figure 14-17).

The cross-bridge theory is able to accountfor the force-velocity curve by assuming thatthe rate constants for the processes ofattachment and detachment of the cross-bridges are dependent upon theinstantaneous position of the cross-bridgerelative to the attachment site on the thinfilament. The rate of attachment is zeroafter the cross-bridge passes the attachmentsite, but the rate of detachment is high. When approaching the attachment site, thecross-bridge cannot attach unless it is withina certain distance; beyond that distance, therate of attachment is zero, but the rate ofdetachment is not. Detachment requires acertain minimum time. At low velocities,there is sufficient time for detachment, but athigh velocities, there may not be. Thus, thecross-bridge may remain attached longerthan it should and actually oppose themovement of the thin filament in thedirection it has just propelled it. This willcause a force opposite in direction to that

4 Another word for force is load.

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caused by sarcomere shortening and,therefore, reduce the effective contractileforce. The greater the velocity, the greaterthe effect of the detachment failure.

Mechanisms for grading force ofcontraction.

We have already discussed onemechanism for grading muscle force, that is,by grading the frequency of discharge in themotoneurons and thus the temporalsummation of twitch contractions. The end-points of this continuum are, of course, asingle twitch in the weakest element (theminimum) and a fused tetanic contraction inthe strongest (the maximum single-unittwitch). Each muscle fiber is contacted byonly one motoneuron, but a motoneuron cancontact many muscle fibers. When amotoneuron discharges, it activates all of themuscle fibers with which it makes synapticcontact. A motoneuron and the musclefibers it contacts are called a motor unit. Amotor unit for muscles of the lower leg maycontain as many as 1700 muscle fibers,whereas a motor unit for the extrinsicmuscles of the eye may contain only 7fibers. The fibers that make up a motor unitare not grouped together in a single bundlewithin the muscle, but are scattered in smallbundles of a few fibers. Thus, forcesproduced by contraction of a single motorunit are distributed through the muscle. Because all of the muscle fibers of a motorunit contract simultaneously, it is moredifficult to achieve fine gradations in theforce of contraction when motor units arelarge. Suppose one motor unit contains 20fibers and another only 5, and suppose eachfiber can produce 1 gram of force. Theminimum forces producible by the motorunits would be 20 grams and 5 grams in atwitch contraction, and temporal summation

would produce forces graded in 20- and 5-gram increments. When fine gradations arenecessary, as they are in eye movements, themotor units are usually small.The force of muscle contraction can also be

varied by varying the number of motor unitsthat are active, i.e., by spatial summation. Because the muscle fibers are connected inparallel and exert force on the same tendon,the forces produced in all the fibers will besummed at the tendon. Therefore, thegreater the number of motor units active thegreater the force on the tendon. Not all ofthe motor units within a muscle are the samesize. As the force of contraction increases,larger and larger motor units are added to thecontracting population. This, of course,means that the force of contraction will be anonlinear function of the number of motorunits. With strong stimulation at rates higher than

5/sec, the force of contraction will increaseover that of the twitches evoked by weak,lower frequency stimulation. This is theresult of both spatial and temporalsummation. The maximum tension a musclecan develop obviously occurs when allmotor units produce fused tetaniccontractions (absolute maximum). Thisoccurs at stimulation frequencies over about50/sec, well within the discharge ratecapabilities of motoneurons. This forms thelimits of control of muscle tension: aminimum of the tension produced by asingle twitch in the smallest motor unit and amaximum of the tension of a fused tetaniccontraction in all motor units. Nearly anyforce in between can be produced by somecombination of contraction of differentmotor units and different motoneurondischarge rates, i.e., different amounts ofspatial and temporal summation..

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A minimum tension is produced by asingle twitch in the smallest motor unitand a maximum by the simultaneousfused tetanic contraction in all motorunits.

Although a motor unit consists ofonly one kind of muscle fiber, mostmuscles are mixtures of FG, SOand FOG fibers.

Tension develops smoothly duringnormal muscle contractions, not at all likethe subtetanic contractions that we haveseen. Yet, motoneurons have stable firingrates over a wide range of developedtensions, and they often fire at rates belowthose necessary to produce tetanic fusion. At these low frequencies, the motor unitsmust behave in a twitchlike fashion. Thismeans that the smoothness of developmentof tension is due to the asynchrony incontraction of different motor units.

Fast and slow muscles.There are two different types of skeletal

muscles in vertebrates, the red and whitemuscles. Red muscles are red because theycontain the protein myoglobin that, likehemoglobin, contains the iron-rich hemegroup. It is the heme group that gives bothhemoglobin and myoglobin a red color andthe ability to bind oxygen. White musclesare white because they contain littlemyoglobin. Red muscles are the moreslowly contracting twitch muscles, the slowmuscles, whereas white muscles are themore rapidly contracting fast muscles. Asalready noted, slow muscles also require alower minimum rate of stimulation fortetanic fusion.

The concentration of myosin is about thesame in both red and white muscle, but theconcentration of myosin-ATPase is muchhigher in white muscle fibers. Red musclecontains many mitochondria and gets mostof its ATP from oxidative phosphorylation.

This source supplies ATP rapidly, and thusthe red muscles are able to sustaincontractions longer without fatiguing. Inaddition, red muscle is highly vascularized,receiving and using more oxygen than whitemuscle. This may also be a function of thehigh concentration of myoglobin. Whitemuscle, on the other hand, contains fewmitochondria and gets most of its ATP fromglycolysis, the breakdown of glycogen(which occurs in high concentration in whitemuscle) into lactic acid. This source of ATPis not as efficient as oxidativephosphorylation, and therefore whitemuscles fatigue more rapidly than redmuscles. White muscle is also more poorlyvascularized. These deficiencies may not bea big problem because white muscles tend tobe active for only short periods in normalbehavior. Because of these differences,white muscles have been called "twitch now,pay later" muscles, whereas red muscleshave been called "pay as you twitch"muscles.

Different muscles contain differenttypes of muscle fibers. Some fiberscontract rapidly, are glycolytic and fatiguerapidly. These are known as FG fibers, forFast, Glycolytic. Other fibers are slowlycontracting, oxidative, and slowly fatiguing.These are known as SO fibers, for Slow,Oxidative. Still other fibers contract rapidlyand are both oxidative and glycolytic and aretherefore known as FOG fibers. Although amotor unit consists of only one kind ofmuscle fiber, most muscles are mixtures of

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FG, SO and FOG fibers. The soleus muscleis a red muscle, and it contains almostexclusively SO fibers (87-100%, dependingupon species), whereas the gastrocnemius, awhite muscle, has a mixture of FG, FOG andSO fibers (41-66%, 14-38%, 5-45%,depending upon species).

The fibers in red and white muscles alsoreceive different innervation. Fibers in redmuscles are innervated by motoneurons ofsmall diameter, thus lower conductionvelocity, that discharge nearly continuouslyat low frequency. Fibers in white musclesreceive innervation from larger motoneuronsthat have longer periods of silence betweendischarges, but discharge at highfrequencies.

The properties of both red and whitemuscles are summarized in Table 14-2. Theproperties of slow muscle fibers make themmost suited to extended periods of

contraction where a minimum force isrequired, e.g., in maintenance of posture. Fast muscle fibers are better suited to shortperiods of rapid contraction at higher forces,e.g., in sprint running. In fact, duringexercise training there may be a differentialeffect on the two types of muscles. Strengthtraining leads to hypertrophy of mainlywhite muscles with conversion of FOG toFG fibers. The number of fibers does notincrease, but the size of fibers and thenumber of myofibrils do increase. Thisincreases both the strength and velocity ofcontraction. Endurance training apparentlyaffects mainly red muscle fibers, causing anincrease in concentration of the enzymes ofoxidative phosphorylation, an increase in thevascularization of the muscle and conversionof FG to FOG fibers, but no change in theratio of fast to slow fibers and no change inmuscle size.

Table 14-2Properties of White and Red Muscles

Property White muscles Red muscles

Twitch contraction time, msec Fast, 50-80 Slow, 100-200

Minimum tetanic frequency 60/sec 16/sec

Myoglobin content Low High

Primary source of ATP Glycolysis Oxidative phosphorylation

Glycogen High Low

Myosin-ATPase activity High Low

Capillary blood flow Low High

Fatiguability Easy Difficult

Nerve fiber size Large Small

Nerve fiber activity Intermittent, high frequency Continuous, low frequency

Tension produced Larger Smaller

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Figure 14-18. Electromyographic records of activity inthe human arm during alternate flexion and extension ofthe elbow. The upper trace shows the EMG from thebiceps, and the lower trace, the EMG from the tricepsmuscle. (Ganong WF: Review of Medical Physiology,7th ed. Los Altos, CA, Lange, 1975)

Figure 14-19. Three-dimensional reconstruction of cardiacmuscle, showing organization of myofibrils, T tubules, andsarcoplasmic reticula. Compare with Fig. 14-5. (WarwickR, Williams PL [ed]: Gray's Anatomy. 35th British ed,Philadelphia, WB Saunders, 1973)

Electromyography.When muscles contract, they generate

action potentials. The action potentialsresult from transmembrane currents inmuscle fibers that can be recordedextracellularly. This may be done inunanesthetized humans using small metalelectrodes on the skin over the muscle orusing hypodermic needle-electrodes insertedinto the muscle. The record of the musclecontraction obtained in this way is theelectromyogram, abbreviated EMG. Whenneedle electrodes are used, it is oftenpossible to detect the discharges in singlemuscle fibers near the electrode. Dischargesin different fibers can sometimes bedistinguished on the basis of the amplitudesof their spikes. Figure 14-18 shows theEMGs from human biceps (upper trace) andtriceps muscles (lower trace) duringalternate flexion and extension of the elbow. Note the spikes of different amplitudes andthe general increase in spike density witheach contraction.

Cardiac muscle.Structurally, cardiac muscle is similar to

skeletal muscle in that it is striated, havingboth thick and thin filaments. It has a well-developed T tubule system, although thesarcoplasmic reticulum is not as large or asextensive as in skeletal muscle. Figure 14-19 shows the basic structure of cardiacmuscle for comparison with Figure 14-5. Unlike those in skeletal muscle, the triads ofcardiac muscle of humans are located at theZ line, giving only one per sarcomere. The

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Figure 14-20. Cardiac muscle action potentials. A. Twoconsecutive action potentials from a pacemaking Purkinjefiber. B. Action potential from a contractile fiber. C. Theupstrokes of Purkinje fiber and contractile fiber actionpotentials shown in expanded sweeps.

mechanism of excitation-contractioncoupling is the same as for skeletal muscle: The membrane action potential leads to anincrease in Ca++ around the myofilamentsthat activates myosin-ATPase and leads tosliding of the thin and thick filaments. Thesource of the calcium is different in cardiacmuscle. Because the sarcoplasmic reticulumis poorly developed, it cannot sequester thelarge amount of calcium that skeletal musclecan. Therefore, much of the calcium forcontraction must come from extracellularsources; it comes in during the actionpotential.

There are a large number of differentkinds of cells in cardiac muscle. Theseinclude cells of the sinoatrial node, theatrioventricular node, the atrium, the bundleof His, and the ventricle, each with adifferently shaped action potential. Thedetails of these differences are beyond thescope of this treatment. For our purposes, itis convenient to distinguish two kinds of

cardiac muscle cells: pacemaker cells, likethe Purkinje fibers, and contractile cells. Examples of a Purkinje fiber action potential(A) and a contractile cell action potential (B)are shown in Figure 14-20. Both actionpotentials are much longer in duration thanspikes in nerve cells and skeletal musclecells, 0.5 sec compared to 0.5 to 5.0 msec. The hypopolarizing phase of the Purkinjefiber's action potential is not different fromthat in skeletal muscle, and it appears tohave the same ionic mechanism, i.e., adramatic increase in sodium conductance. The rising phase of the contractile cell'saction potential is shown in an expandedsweep in Figure 14-20C (right) along withthat of the Purkinje fiber for comparison5. The contractile cell's action potential hastwo rising phases, a rapidly rising phase, likethat in the Purkinje fiber6, and a more slowlyrising phase. The fast phase has the samemechanism as the rising phase of Purkinjefiber action potentials, but the slower phaseis the result of a slow inward current, carriedmostly by Ca++. Calcium current activationoccurs at a more hypopolarized level of themembrane potential than does sodiumactivation, and the inactivation of thecalcium current is less rapid by about twoorders of magnitude.The long plateau of the action potential in

cardiac muscle serves two functions: Itprovides a more prolonged contractionwithout resorting to tetanus, and it providesa longer refractory period to prevent theheart from contracting prematurely. This

5 The differences are exaggerated in thisfigure for didactic purposes.

6 Do not confuse the Purkinje fibers(muscle) of the heart with Purkinje cells(nerve) of the cerebellum.

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In pacemaker cells, the membranepotential is almost always changing; sothere is no true resting potential. Figure 14-21. A scheme that explains the form of the

Purkinje fiber action potential and the pacemaking activity.Two consecutive Purkinje fiber action potentials are shownin A. Changes in sodium and potassium conductancesduring the action potential are shown in B. The ordinatesare membrane potential (A) and membrane conductance(B); abscissa is time. (Noble D: J Physiol (Lond)160:317-352, 1962)

plateau is produced by a number of factors,the most important of which is a decrease inpotassium conductance withhypopolarization, followed by a slowlydeveloping increase that brings thepotassium conductance to a final value justslightly greater than resting levels inPurkinje fibers and to resting levels incontractile cells in about 300 msec. Achange in membrane conductance withchanges in membrane potential is calledrectification by biophysicists. This changein potassium conductance is calledanomalous rectification.

Changes in sodium and potassiumconductances are shown in Figure 14-21Bon the same time scale as the Purkinje fiberaction potential in A. During the plateau ofthe action potential, membrane resistance ishigh. Thus, after the peak of the actionpotential, gNa+ begins to decrease, albeitmore slowly than in skeletal muscle andnerve, and in contractile cells the slowinward current persists. In addition, theremay be a small outward current due tochloride ions7. These currents would beeffectively canceled by a big outward K+

current if the potassium conductanceremained normal, but, because gK+ isdepressed due to anomalous rectification,the sum of the outward iK+ and outward iCl-

is just slightly larger than inward sum iNa+ +iCa++, and the membrane repolarizes onlyvery slowly. However, as gK+ increasesduring the spike (because the membrane isslowly repolarizing), iK+ increases whilegNa+ and gCa++ are decreasing, and themembrane begins to repolarize faster andfaster (the downstroke of the actionpotential) until the resting membranepotential, Vr , is reached.

In Purkinje fibers, the membrane really has

7 The chloride current is outward becausethe driving force at the plateau is outward(the membrane potential is positive outside);chloride ions actually enter the cell.

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Figure 14-22. Length-tension curve for cardiac muscle. See legendfor Fig. 14-15 for details. Note that the maximum force is notdeveloped at the resting length but at a length longer than the restinglength.

no Vr because the membrane potential isconstantly changing. This is a property ofpacemaker cells, cells that have their ownintrinsic rhythms of activity. As soon as oneaction potential is completed, the membraneimmediately begins to generate another,even in the absence of any neuralconnections. This kind of behavior is neverfound in skeletal muscle; the muscle doesnot contract in the absence of innervation. When the Purkinje fiber membranerepolarizes, it returns to the maximumnegative diastolic membrane potential, Vd,where membrane current is zero, im=0, but itstays there only for an instant before themembrane begins to hypopolarize again. AtVd, the membrane current is zero becausethe outward potassium current is exactlybalanced by inward sodium, calcium andchloride currents. The membrane begins tohypopolarize because the potassiumconductance, after its initial decrease andslow rise to a level just higher than restinglevel, begins to decrease toward restinglevel. As it does so, the potassium currentdecreases and a point is reached where iK+no longer balances the inward currents, andthe net inward current hypopolarizes themembrane. When the critical firing level isreached, the action potential is initiated. Thepacemaker rhythm that develops ismyogenic (of muscle origin) rather thanneurogenic (of neural origin), but it can beinfluenced by neurotransmitters; thesedecrease or increase the rate of formation ofaction potentials by decreasing or increasingthe rate of hypopolarization after the actionpotential. With increased rate, thesucceeding action potential begins sooner;with decreased rate, it begins later.

Not all muscle cells are pacemaker cells,but the whole heart must behave as a unit forit to be an effective pump. Contractions are

partly synchronized by electrotonic spread ofaction potentials from one cell to another. Heart muscle is a network of branchingmuscle fibers connected to each other by gap

junctions that are strung together in astructure called the intercalated disk. Anintercalated disk is shown in Figure 14-19. The gap junction is thought to be a lowimpedance pathway, much like anelectrotonic synapse. It seems likely thattransmission of the action potential fromcell-to-cell in cardiac muscle is the same astransmission from cell-to-cell at anelectrotonic synapse.

Cardiac muscle behaves much like skeletalmuscle, but it exerts a passive tension whenstretched at much shorter lengths. In fact,when the muscle is stretched from a lengtheven shorter than resting length, there is aresistance to the stretch. In other words,

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Cardiac muscle differs from skeletalmuscle in its structure, in the sourceof its calcium and in the fact that itcan develop tension at lengths lessthan resting length.

cardiac muscle experiences elastic tensioneven at resting length (skeletal muscle doesnot). In addition, the maximum developedtension in cardiac muscle occurs, not at theresting length, but when it is stretchedbeyond resting length (Figure 14-22). Theresult is that when more blood returns to theheart from the veins, the muscle fibers of theheart will be stretched more, and the bloodwill automatically be pumped out moreforcefully than when the heart is justnormally full. This is the basis of the Frank-Starling mechanism in the heart.

The force-velocity curve for cardiacmuscle has the same shape as that forskeletal muscle and similar parallel curvesare generated for different initial lengths,with a constant Vmax. Increasing the amountof blood in the heart, therefore, does notincrease the contractile ability orcontractility of the muscle. On the otherhand, the actions of certain agents likenorepinephrine or circulating hormonesinclude increasing Vmax or contractility ofcardiac muscle.

Smooth muscle.There is considerable diversity among

smooth muscles, but all share a lack of thecross-striations characteristic of cardiac andskeletal muscle and an innervation by fibersof the autonomic nervous system likecardiac muscle. This is unlike skeletalmuscle that is innervated by fibers of thesomatic system. Smooth muscle fibers aresmaller than skeletal muscle fibers and are

filled with filaments oriented approximatelyalong the long axis of the fiber. There areboth thick, myosin-containing filaments andthin, actin-containing filaments, but they arenot interdigitated like those in striatedmuscle. The thin filaments appear to beattached to the plasma membrane or to somestructure in the cytoplasm. In general, thereis twice as much actin but only one-third asmuch myosin in smooth muscle as in striatedmuscle.Smooth muscles develop tension that

varies with muscle length in a mannersimilar to that in skeletal muscle, but over amuch wider range of muscle lengths, nearlytwice that of skeletal muscles. This propertyis appropriate for their functions as liningsof hollow organs; even when the organ isgreatly distended, smooth muscles can stillexert considerable tension. Many peopleassume that the presence of a length-tensioncurve implies that contraction occurs by asliding filament mechanism, but how thisoccurs is not known. It has been shown thatsubstantial tension can be developed inmyofibrils to which myosin heads have beenadded in the presence of Ca++ and ATP, butin which thick filaments are absent (OplatkaA, Gadasi H, Borejdo J: Biochem BiophysRes Comm 58:905-912, 1974). This couldbe related to the contraction mechanism insmooth muscle.Stretching a denervated smooth muscle

causes it to actively contract, a phenomenonnever seen in skeletal muscle. Presumably,stretching, like the occurrence of an actionpotential, causes an increase in cytoplasmicCa++ that comes either from the sarcoplasmicreticulum or directly across the cellmembrane. Smooth muscle contraction ismuch slower than that of skeletal muscle. This may be due to slow diffusion of Ca++

from outside the cell or to the slow rate of

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ATP hydrolysis or both.Smooth muscle, like cardiac muscle,

undergoes spontaneous, rhythmiccontraction, driven by activity in certainpacemaker cells that behave like pacemakercells in cardiac muscle. This pacemakeractivity is conducted through gap junctionsto neighboring smooth muscle fibers that donot generate pacemaker activity. This istypical of a type of smooth muscle calledsingle-unit smooth muscle. Contractileactivity of single-unit smooth muscle can bealtered by nerve activity or hormones. Thiskind of smooth muscle also contracts inresponse to rapid stretching. Single-unitsmooth muscles are found in intestinal tract,uterus, and blood vessels.

Multi-unit smooth muscles are found inthe lungs, arteries, and erectile tissues of hairfollicles. These smooth muscles contain fewgap junctions, and therefore contractions donot spread from cell-to-cell as in single-unitsmooth muscle. Multi-unit smooth muscleis richly innervated, with each cell receivinginnervation from more than one nerve fiberand each fiber innervating several cells. Like skeletal muscle, multi-unit smoothmuscle has motor units; unlike skeletalmuscle, the neural inputs to these smoothmuscles can be either excitatory orinhibitory. The response of the wholemuscle depends upon the number of motorunits active, the frequency of discharge inthe fibers and the relative amount ofexcitatory and inhibitory input. Multi-unitsmooth muscle activity can be initiated byhormones, but it is not much affected byrapidly stretching the muscle.

SummaryUnder normal circumstances, contraction

of skeletal muscle is initiated by actionpotentials in motoneurons which arrive at

the neuromuscular junction and cause therelease of acetylcholine from their terminals. The acetylcholine produces in the muscle, ahypopolarizing postsynaptic potential, theend-plate potential, which always initiatesan action potential in the normal musclefiber with normal innervation. The muscleaction potential sweeps down the musclemembrane into the T tubules and somehowcauses release of calcium from the cisternaeof the sarcoplasmic reticulum. Calciumbinds to troponin, and there is a release ofinhibition of myosin ATPase, hydrolysis ofATP, and relative translation (sliding) ofthick and thin filaments, causing thesarcomere to shorten and tension in themuscle to increase and perhaps causing themuscle to shorten. It is thought that actuallinkages are formed between thick and thinfilaments (cross-bridges), and the cross-bridges rotate. Contractions are terminatedby removal of calcium from the sarcoplasminto the thin longitudinal tubules of thesarcoplasmic reticulum. The cross-bridgetheory maintains that relaxation occurs whenthe cross-bridges are disconnected, the serieselastic elements then restore the muscle toresting length.Muscle contraction can be isometric or

isotonic in the experimental situation. Isometric contractions are those wheretension develops in the muscle, but it doesnot change length. Isotonic contractions arethose in which the muscle experiences aconstant tension, but may shorten. Duringmovement, muscle contraction is probably amixture of contractions that are isotonic,isometric, and neither, with both length andtension varying.A single action potential in a motoneuron

will initiate a short, twitch contraction in themuscle that it innervates. If several actionpotentials arrive at the muscle close together

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in time, the twitches may sum. Summationmay result in a sustained contraction that isknown as tetanus.

Striated muscles develop their maximumisometric tensions at their resting lengthsand develop only smaller tensions at lengthsgreater or less than resting length. Thevelocity of shortening of a muscle dependsupon its load, the greater the load, the lowerthe velocity. Expressed another way, thegreater the velocity of shortening, thesmaller is the load that can be lifted by themuscle.

The force of muscle contraction can begraded by changing the frequency ofdischarge in active motor units and bychanging the number of active motor units,resulting in forces graded between thetension of a twitch in the smallest motor unitto the tension of a fused tetanus in all motorunits of the muscle.

Fast muscle is distinct from slow musclein its faster twitch contractions, highermaximum tetanic frequencies, lowermyoglobin content, lower blood flow, easierfatiguability, and innervation by larger axonsthat discharge intermittently at higherfrequency. A motor unit contains either fastor slow muscle fibers, but a muscle isusually a mixture of both fast and slowfibers.

The EMG is a recording of the actionpotentials of groups of muscle fibers that lienear the recording electrodes. If needleelectrodes are used to record the EMG, thedischarges of single fibers can often bedistinguished.

Cardiac muscle differs from skeletalmuscle in the shape of its action potentials. All action potentials in cardiac muscle aremore slowly developing (thehypopolarization phase is longer) and oflonger duration. These differences are due,

at least in part, to the slow inward calciumcurrent and perhaps different channelactivation kinetics and to anomalousrectification, respectively. Cardiac musclealso shows rhythmic activity that ismyogenic, never seen in skeletal muscle. Also unlike skeletal muscle, cardiac muscleexperiences elastic tension even at restinglength and is able to develop tension atlengths shorter than resting length.Smooth muscle behaves either as a single

unit, i.e., there are many gap junctionscausing the whole muscle to contract more-or-less at once, or as multiple units, i.e.,there are few gap junctions, but richinnervation, each cell capable of inde-pendent contraction. In single-unit smoothmuscle, rhythmic contractions are myogenic;in multi-unit smooth muscle they areneurogenic. Single-unit smooth musclecontracts in response to rapid stretch; multi-unit smooth muscle does not.

Suggested Reading1. Ariano MA, Armstrong RB, Edgerton

VR: Hindlimb muscle fiberpopulations of five mammals. JHistochem Cytochem 21:51-55, 1973.

2. Bendall JR: Muscles, Molecules andMovement. New York, American Elsevier, 1970.

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