CHAPTER9

Cellular Physiology
of Skeletal, Cardi dc,
and Smooth Muscle
Michael Apkon

L-

ri"l'l

::;!1{gi;.t

,t|i..li'.,

.:t:l;a::.,

,l

The primary function of each of the three fundamental types of muscle. l , e l e t " .c a " J . r c ". d - r o o t h m u s ,l - r . t o B p n e l a l lco r . e . ' r n o , , e n e - t
responseLo a physlological stimulus. All muscles transduce a chemical or
electricalcommand into a mechanicalresponse.However, the unique physiologicaL lole ol each of the three basic muscle types dictates rnherent
dillerencesin the rate and duration of contraction, metabollsm, fatigabrLiry,
and tl.re ability to regulare contractiLesrrengrh. For cxample. boLh skeletaL
and cardiac muscle must be capableol rapid force cler.eLopment
and shorl
ening. However, skeletal muscle must be able to maintain contractile force
for relatively long periods, whereas cardiac muscle need onLy contract
briefly wiLh each heartbeat, although it must sustain Lhis periodic acnvty
for an entire lif.etime.Smooth muscle, like skeletal muscle, must be able to
regulatecontractionover a lvide rangr of folce Horvever',
rn some tissues
(e.g snhincrcrs)smoorhmusclernust be able to sustaincontractionwitho rr l : r i o e
r l o ' . c n l n n o n p r i n d . l n . n r , o f r h r * n l f e r c .np. r r.h.p r. frl g q e r
for muscle contraction is the same for all three types of muscle: a rise rn
the freecylosoLicCa'z-concentration([Ca'z-],).
In muscle of all types, certain comnonents of the mnsrle cell are highly
specializedto accomplish the muscle'sunique lunctiolr. Given the dispanry
in their physiological roles, it is not surprising that eacl.rmuscle type has
evolved unique anatomic structures and functionaLmechanisms.Thus, the
v J r o u - \ , p e >o l n u . . " c e l , L l , e . p e . a l t - , d p h s m J 1 . . r b r " n e ( ) l o , , e
eLons,endoplasmic reticulum, and metabolic pathways for energy generation and utilizatLon.

EXCITATIONOF MUSCLECEttS

?
).t

The plasmamembrane or sarcoLemma-of each of the t1-pesof muscle

celis has regions that are specializedLo facihtate communication betweer.i
ceLls.ln skeletrlmuscle,this specialization
LakesLheform of the postslnaplic portion of the neuromuscularjunctior-r Neuromuscularjunctions(i.e.,
chemical sy-Lapses)are also present in cardiac and smootlr muscle. ln
cardiac muscle, neuromusculartransmissiol-tcloesnot iniLiaLecontraction; il
only modulatesil. On the other hand, neuromuscular transmission may
rnitiale contraction in smooth muscle ceLls,or it may modulate conlraclion
that has been initiared by another mechanism.In both smooth and cardiac
musclecells,grp.lunLtions(i e . electricalsynapses)
couple the sarcolemma
o[ nerghbonng ceL]s: these also play an rmportant role in intercellular
communlcanon.
230

CellularPhysiologyof Skeletal,Cardiac,and Smooth Muscle / 9

lntercalaied
disk

Branchedstructureof cardiacmuscle

l\,4
icrofibril

Intercalateddisk

--:-*-;
i Desmosome

ses to modulate, rather than to inltiate, cardiac muscle

function. ln contfast to skeletal muscLe,cardiac muscle

contraction is triggered by electrical signals from neigh
boring cardiac muscle celLs.Theseelectricalimpulses originale in the pacemaker region of the heart, the sinoatrial
node (p. 489), which spontaneouslyand periodically generatesaclion potentiaLs.To facilitate direct electricalcommunication between cardiac muscle cells, the sarcolemma
o f , a r J t " , .m u s c l eI < < p e i.a l i z e dr o c o n L d i ng a p j u n c l t o n .
(p. 164), electrical s).Tiapses
that couple neighboring cells
(Fig. 9-1). When an action potential is initiated in one
cell, current flows through the gap junctions and depolarizes neighboring cells. If depolarization causesthe membrane potential (V-) to be more positrve than threshold,
self-propagatingaction potentials occur in the neighboring
cells as well. Thus, the generationof an action potential is
just as critical 1or initiating contraction in cardiac muscle
as it is in skeLetalrnuscle.

Smooth MusclesMay Contract in Responseto

Either NeuromuscularSynapticTransmission
or ElectricalCoupling

Z-line
FICURE9-1.

2r1

Electricalcoupling of cardiac myocyles

SkeletalMuscleContractsin Response
to
SynapticTransmission
Neuromuscular
The mature skeLetalmuscle cell has a sinsle neuromuscud r - u n c L i o \n l ' e r ed r e L ) . c L o l irnAe( h ' r e i e p t o r .r r e . o n centrated(p.209). A singlemuscLecell respondsto only
a single neuron. However, a single neuronal axon may
bifurcate to innerrratesevera]individual muscle cells. The
group of muscle ceLlsinneruated by a single neuron is
referred to as a motor unit.
The neuromuscularjuncrion is the focus of Chapter B.
Bnefiy, the ACh releasedby the preslnaptic nene terminal binds to inotropic (nicotinic) ACh receptors at the
neuromuscularjunction. These receptors are nonselective
cation channels that open when ACh binds to a specific
site on the channel, and a depola zation known as the
end-plate potential is produced. I[ this end-plate poten
tial exceedsthe threshold for activatins Na+ channels.an
d . r i o F p o r e l , . j r p - u l l >t r e n e r a l t o o
nl in ac on potenrial
initiates the sequenceof processesleading to contraction.
The ACh ls rapidLy inaclivated by acetylcholinesterase,
an
enz)rme lhat is manufactured by the muscle ceLL,and
muscLecontraction stops a few millisecondsafter neuronal
acilvity ceases.

CardiacMuscleContractsin Response
to the
Propagationof Electrical
Signalsfrom One
CardiacCellto AnotherAcrossGaplunctions
Cardiac muscle cells also have chemical sl'napses.but the
5 y n l d t L e lc a r d p a r a . l n p a t h e t i ,b r a r c h e st l r F e a u L o
n o l c n e r \ o L << v s r e nl : e c C h a p t e rl 5 ) u i e r h e s eq ) m a p -

Like skeletal muscle, smooth rnuscle receivessynaptic input from the neryous system. However, the q.naptic input to smooth muscle differs from that to skeletalmuscle
in two ways- First, the neurons are part of the autonomic
n p n o u c s y s l e mr a t h e rt h a - L h e' o m a t i c n e r v o u .s y s t e m
(see Chapter 15). Second, the neuron makes multiple
contacts with a smooth muscle cell. At each contact
pornt, the axon diameter expands to form a varicosity
that contains the presynapticmachinery. The varicosity is
in close proximity io the postslrlaptic membrane of the
smooth muscle cell, but there is relatively little specialization of the posts).napticmembrane. Rather than the neurotransmitter receptorsbeing closely clusteredat the neuromuscular junction, as in skeLetalmuscle, in smooth
muscle the receptors are spread more wideLy across the
posts).naptrcmembrane.
The mechanismsof intercellular communication among
smoolh muscLecells are more diverse than are those of
. L e l e t a ol r c a r d r a cm u s ce I n ' o n e o - g a - ' . 5 m o oh m u < cle is innervated in a manner similar to skeletaLmuscle in
r h " r e a c h s m o o r h m u " c l e c e l l r e c e r r e <5 ) ' n a p l ' ci n p u l
However, a difference is that a smooth muscle cell may
receive input from more than one neuron. Moreover,
there is little electrical coupling among these smooth
muscle ceLls (i.e., few gap junctions). As a result, each
smoolh muscle cell may contract independently of its
neighbor. Becausethis type of smooth rnuscle behavesas
multiple, independent celLsor groups of ceLls,it is called
multiunit smooth muscle (Fig. 9-2A). Note that the
"multi" in "multiunit" refers to lhe muscle fibers' acting
independently of one another as multiple unirs. Muhiunil
smooth musclesare capableof finer control. Indeed, multiunit smooth muscle is found in the iris and ciliary body
of the eye, the piloerector muscles of the skin, and some
blood vessels.
ln contrast to multiunit smooth muscle, the smootll
muscle cells of most organs have extensive intercellular
communication in the manner of cardiac muscle cells. ln

9 / CellularPhysiology
of Skeletal,
Cafdiac,and SmoothMuscle
A

I,4ULIIUNIT
I,4ULIIUNIT

UNITARY

Elechicalisolation
of cells allows finer
motor control,

Autonomicneurons/.

Smoothniusclecetl

Varicosilies
(synaptic
contacts)

FICURE 9-2. Smooth-muscle organization. A, Each smoolh muscle celL receives its own s'naptic inpuL B, Only a ferv of the snooth muscle cells
receivedirect s\taDlrc rnDut.

tl.ris tlpe of smooth muscle, gap junclions permit electd

cal communication between neighboring cells. This communication alLowscoordinated contractior-rof many celLs.
Becausethese cells contract as a single unil, rhis tlpe of
smoolh muscle is called unitary smooth muscle (Fig. 9
2B). Unitary smooth muscle is the predominant smooth
r.ru5cle lpe wtthin Lhe wall, oI r s.e-a] orga . ,u, h a,
the gastrointestinaLtract, the uterus, and many blood vessels. For this reason, unltary smooth muscle is often referred to as visceral smooth muscle. Among unitary
smooth muscles, variation in the strength of intercellular
coupling from organ to organ leads to VariaLionin the
spatial exlent ol a single unit. For example, in Lhe bladd e r . e r t e n -r e c o u p l i n ga m o r g , . e l l sd e n n e , a g e l u r r L
rional units, which allows the muscular wall o[ the bladd c r t o . o n t r a , i n s ; n . h r o n 1O
. n rhe orher
rh,
- m o o r h m u s . l p c e l s o l b l o o d v e > s e l ic o u p l e"Lnod .o r n smaller, independently lunctioning units that are more
akin to multiunit smooth muscLe.ln fact, electrical cou
pling of smooth muscle unjts exhibits a tissue-specifrc
conlinuum f.rom multiunit to unitary couphng.

a smooth muscle cell capable of producing an action

polenlial an action potentlal will then ensue.
Action potentials are usualLyseen in unitary (visceral)
smooth muscle. These action potentials typically have a
slower upsLroke and longer duration (up to -100 ms)
than do skeletal muscle acrion porentials (-2 ms). The
action potential in a smoolh n]uscle celL can be a simpLe
spike, a spike foLlowedby a plateau, or a seriesof spikes
on top of slow waves of V- (Fig. 9 3A). In any case,the
upstroke or depolarizing phase of the action potential
reflects opening of voltage gated Ca2* channels. The inward Caz* current further depolarizes rhe cell and
thereby causesstill more voLtage-gatedCa2* channels to
o p e . T h u . . 5 o n e 5 m o o r hm u s c l e. e l l s , a n u n o c r g ot h e
same tlpe ol regenerativedepoLadzationthat is seen in
skeletal muscle. However, the rate o[ rrse of the action
potential in smooth muscle is lower becauseCa2* chan
nels open more slowly than do Na* channels in skeleral
and cardiac muscle (p. 189). Repolarlzationof the smooth
muscle ceLl is also relatively slorv. Two explanationsmay
b e o ' [ e o d [ o - L h i s . l o w e r r e p o l a r - - t l o n .t i - : r . \ o l l J g c gated Ca']- channels,which are responsiblelor the depo,
larization phase of the action potential, inacrivareslowly.
Action Potentialsof Smooth MusclesMay Be
Seconcl,the repolarization phase of the action potenrial
Brief or Prolonged
r e l l e c r 'L h ed e l r \ e d d c t r \ d t l o no l r o l r a g e - g a L e
Ko' . h a n Whereasboth skeletalmuscle and cardiacmuscle procluce
nels and, in some cases,Ca2* activatedK* channels.
actron potentials that iniliale contraction, smooth muscle
Some smooth muscle cells have fast, voltage-gatedNat
cells produce a wide range o[ V., variations that can
channels.
Howerer, even when these channels are
either initiate or modulate contraction. Acrion poientials
present,
they
do not appear to be necessaryfor generating
thai are similar to rhose seen in skeletal muscle are ob
potenlial.
ar.r
aclion
Their main role may be to allow more
seNed in unitary smooth muscle and in some multlunit
rapid
actnation
of
voLtage-gated
Ca,+ channels and thus
Like
cardiac
muscle.
muscLecelis, some smooth muscle
contdbute to a fasterrate of depolarization.
cells exhibit prolonged aclion potentials that are characIn some unilarl' smooth muscle, repolarization is so
terized by a prominent plateau. Still other smoorh muscle
that the action porential contour displaysa promdelayed
cells cannot generate action potenrials at all. In these
inent
plateau.
These plateau porentials may be several
(p.
celLs,V^ changesin a graded fashion
173) rather rhan
hundred mllliseconds in duration, as in cardiac muscle.
in the all-or-none manner of action potentials.The stimuli
Plateau action potenrials occur in smooth muscle of Lhe
that produce a graded response of V," include many
genilourinary tr-act, including the ureters, bladder, and
circulating and Localhumoral factors, as welL as mechanical stimuli such as stretching the cell. These graded V.
uterus. The long V- plateau allows the entry of Ca2* to
.hange, .rar be eiiherh\petpoiarizing
o c e o o l a r r z r n g . continue for a longer period and thus alLows lCa,*j, to
they sum lemporaily as well as spatially. lf the summation
remaln high for a longer period, thereby prolonging rhe
of graded depolarizationsbrings V," above threshold-in
contractlon-

CellularPhysiologyof Skeletal,Cardiaq and Smooth Muscle / 9

A TYPESOF SI\,IOOTH.MUSCLE
ACTIONPOTENTIALS
Slowwaves

+10
0
_10
-50
-90
0 100 0
200 400
Time(rnsec)
Time(msec)

10
Time(sec)

B GENERATION
OF SLOWWAVES

al
Voltage-gated Ca2+
clnnnels open

---------------- -----rActionpotentialspiler
I

Ca2t influx, [e in internal

Ca" concentration

Voltage-gated Ca" charmels close;

internal Ca'- concentration decreases

Open Ca'--dependent
K" channels

Slow hlTerpolarization

FICURE 9 3. Action potntials and slow waves in smooth muscle

9 / CellularPhysiologyof Skeletal,Cardiac,and Smooth l\4uscle

SomeSmoothMuscleCellsCan Initiate
Electrical
Activity
Spontaneous
Although smooth muscle cells undergo changesin V- in
responseto neuraL,hormonal, or mechanicaLstimulation,
many smooth muscLecells are capable of initiating sponlaneous electrical activity. In some ceLLs,
this spontaneous
activity results from pacemaker currents. These currents
result from time- and voltage-dependentproperties of ion
currents that produce either a spontaneous increase in
i n w a r d o r d e p o l ai z r n g .c u r r e n r r. e . g r o l t a g eg a r e dC a cufients) or a spontaneousdecreasein ouiward, or hyperp o l a - r z i n gc.u r r e n l sr e . g . .v o L a g eg a r e dK ' c u r r e n L sT) h e
pacemakercurents cause the cell to depolarize unril Vr e a c h et' h r e . h o l dI.r i g g e r - gJ n a c r r o np o t e n L i a l .
ln other smooth muscle cells, this spontaneouselectrical activity results in regular, repeddve oscillationsin V-.
These 4, osclllationsoccur at a frequency of severaLoscillations per minute and are referred to as slow waves
(Fig. 9 3B). One hyporhesis for the origin of slow-wave
potentials suggeststhat voltage-gatedCa2+channels-acrive /l

rhc

restino V

-dennlatoe

end-plate potential in skeletal muscle. Junctional potent i a l ' ' p r e a d e l e c t r o t o - r c a l l,i . e . i n a g - a d e d f a s "o n r
throughout ihe muscle fiber, thereby altering V- and afl e c t i n g r h e e n t r y o f C a 2 t h r o u g l v o l r a g e - g a r e: lco r , r
(L+1pe) Ca':* channels.Changesin V--by
an unknown
T e c h a n i ) m m a 1 a l , o m o d u L a r reh e a , r . r t y o f L h e e n
z1-mephospholipase C, which cleaves phosphoinositides
to releasethe intracellular second messengersdiacylglycerol (DAG) and IP, (p. 100). Both these second messengers are modulators of contractile force. In the absenceof
action potentials, some unitary smooth muscle, including
some vascularsmooth muscle, also contractsas a result of
graded V- changes.
Some smooth muscle cells conrract without any change
in V-. For example, a neurotransmifter can bind to a
receptor, activate a G protein, and lead to the generation
of lPr, which in turn leads to the releaseof Ca,* from the
SR. The eventual depletion of Ca2* stores in the SR may
in tum stimulate Ca2* influx across the cell membrane
via so-calledstore-operated Ca2t channels.
@

rhe cp I prnrroh r^

activate more voltage-gatedCa2* channels.This activation

results in progressivedepolarizationand Ca'?*influx. The
increasein [Ca'?+],activatesCa'z*dependenr Kn channels,
which leads to progrcssivehyperpolarizationand rermina
tion of the depolarizationphase of the wave. These pei
odic depolarizationsand [Ca'?t],increasescause periodic,
tonic contmctions of the smooth muscle. When the amplitude of the slow V", waves is suff,cienr to depolarize
the cell to threshold, the ensuing action potentials lead to
f l r l L e r e a ' t n f l u xa n d o h a 5 i c o n t r a c r r o n . .
Other hlpotheses to ixplain spontaneouseLectricaland
mechanical activity in smooth muscle cells are based on
oscillaiorJ changes in other intracellular ions or molecules. For example, increased [Ca,*], during an action
potenlial mighr stimulale Na-Ca exchangeand lead to a
cyclic increasein lNa*1, and rhus an increasein the rate
of Na* extrusron by the electrogenicNa-K pump Alternatively, the inositoL 1,4,5-triphosphate(lP) recepror channel (p. 100) might spontaneousLyopen and reLeaseCar*.
The effect on [Ca2*],would be self-reinforcingbecauseof
Ca' -acrivaledCa) releaseria Lhe lP, recepLorAr nigl[Ca,*j,, this channel is inhibired and rhe Car+ release
event is terminated, followed by re-uptake of Ca2* into
the sarcoplasmic reticulum (SR). The fCa']*], increases
may rhemselveslead to periodic electical activily by stim
inward and outward currents.
ulating Ca'z*-activated

Some Smooth MusclesContract Without

Action Potentials
Whereas action-potentialgenerationis essentialfor initiatrng contraction of skeletal and cardiac muscle, many
smoolh muscle cells contract despite being unable to gen
erate an aclion potential. As discussedpreviously, V- oscillations can lead to tonic contractions in rhe absenceof
action potentials. Action potendals usually do not occur
in multiunit smooth muscle. For example,ln the smooth
muscle that regulatesthe ids, excitatory neurotransmitters
such as norepinephrine or ACh cause a local depolariza,
tion, rhe junctional potential, which is similar to the

MUSCLECONTRACTION
StriatedMuscleCellsAre DenselyPacked
with MyofibrilsThat ContainOrderedArrays
of Thickand Thin Filaments
As summarized in Figure 9 44, each individual skeletal
muscle cell (or myacjte or rfiber) contains a dense parallel
array of smaller, cylindrical elements called myofibrils
that have the diamerer of a Z disk (p. 45). Each of these
myoEbrils compises repeating units, or sarcomeres, that
consist o[ smaller interdigitating filaments called myofilaments. These myofilaments come in two q.pes (see Fig.
9-4B), thick fiLamentscomposedprimarily of myosin and
thin filaments composed primarily of actin (p. 27). The
sarcomere extends from one Z disk to another. Sarcomeres stacked end to end make uo a mvofibril. The
reoeaLingsarcomeresare rro5l l-ighli organrzecwiLhin
skeletal and cardiac muscle and lmpan a striped appearance. Thus, both skeletal and cardiac muscle are referred
to as striated muscle.
ln smooth muscle, striations are not vlsible. Although
actin and myosin are present in smooth muscle cells, the
relationship between actin and myosin (lhin and thick
filaments) is less highLy organized.The actin filaments are
oriented mainLyparallel or obLiqueto rhe long axis of the
cell. Multiple acdn filaments appear to join ar electrondense regions called dense bodies, which are found im
mediateLybeneath the celL membrane, as well as within
the inteior ol the myocyte. The rhick frlamentsare lnterspersedamong the thin frlamentsin smooth muscle, and
are far less abundant than in skeletalor cardiac muscle.
Thin filaments are 5 ro B nm in diameter and, in
striared muscle, 1 p,m in length. ln stiated muscle, the
thin filaments are tethered together at one end, where
they project from a dense disk known as the Z disk. The
Z disk is oriented perpendicular to the axis of the muscle
fiber; thin hlamenti pioject from both its faces.Nor only
do Z disks lelher the thin fi.lamentsof a sinele mvofibriL
t o g e t h e rb u t c o n n e c r r o nore L w e etnh e Z d i < l - sa s o t e L h e -

of Skeletal,
Cafdiac,and SmoothMLrscle
CellularPhysiology
/ 9
A

TO I\i]YOFILAMENTS
FROMIV]USCLE

tvloDELOF A SARCOI\iIERE

A oano

Z ine

cr-Actinin
One sarcomeTe

ELECTRONI\,lICBOGBAPH
OF SABCOIVEBf

H band

I band

thiniilamenls
(myofilaments)
Onesarcomere
FICURE 9-4.

Structure of the sarcomere.

each myoflbril to its neighbors. These interconneclions

align the sarcomeresand give skeletal and, to a lesser
extent, cardiac muscle i|s slriated appearance.
The thick filaments are l0 nm in drameter and, in
striated muscle, 1.6 pm in Length.They lie between and
partially interdigitate with the thin filaments. Thrs partial
inrerdigitarlon results in ahernaung 1lghLand dark bands
along the axis of the uryofibril (see Fig. 9 4C). The [ght
bands, which represent regions of the thin hlament thar
d o - o r l r e a l o n g s i o et c ( h l a m e n' . a r e l . o w - a . I
bands becausethey are isorropicto polarized hght. The Z
disk is visibLeas a dark perpendicular Lineat the center of
rhe I band. The dark bands, which representthe myosin
filaments. are known as A bands becausethey are aniso
rropic to polarized light. During contraction, the A bands
are unchangedin length whereasthe I bands shorten.
Wirhin the A bands, the pivoting heads of the thick
myosin filaments, the moiecular motors, establish crossbridges to the thin actin filaments. As drscussedLater,the
adenosinetriphosphate (ATP)-dependent cycle of n.iaking
and breaking cross bridges causesthe actin filament to be

drar,r,nover rhe myosin filament and rhereby resulb in

muscle contraction.

The Thin and Thick FilamentsAre

Supramolecular
Assemblies
of
ProteinSubunits
THIN TILAMENTS.
Tl.un filaments (Fig. 9 5A) consist of
actin, tropomyosrn, and troponin. The backbone of the
fllament is a doubLe-strandeda-heLicalpol1'rnerof actin
molecules.Each helical turn of a single strand of filamentous or F-actin consistsof 13 indivldual actin monomers
and is approximately 70 nm lor.rg. F-actin is associated
r,vith trvo important regulatory, actin-binding proteins:
erd

trnnnnin

lndir'1dual tropomyosin moleculesconsist of two ider.rtical o helices that coil around each other and sit near the
Lwo grooves that are tormed by the two hellcal actin
strands. Head-to-tail contacr between neighboring tropomyosin molecuLesresuLtsin two nearly continuous helical

236

9 / CellularPhysiologyof Skeletal,Cardiac,and Smooth Muscle

A THINFILAMENT
i<__

ca2*(oouno
i
to troponin\
complex) \

70 nm
Troponin^complex
TnT TnC TnI

Tropomyosin

Actin

B MYOSINMOLECULE
Heads of myosin
heavychain(Sr)

Regulatory
lightchain

AIkali
lightchain
ot heavy chains
Tail regionof heavy chains
C

INTERACTION
OF THINAND IHICK FILAIV]ENTS

myosin-ll molecules. Each myosin-ll molecule is a hexamer (actually a double trimer) composed of two intertwined heavy chriins,rwo regulatorylight chains,and two
alhali (or esseixtial)lighr chcins. The two healry chains
have three regions: a rod, a hinge, and a head region. The
rod portions are a helices thar wrap around each orher.
At the hingeregions, rhe molecule flares open ro form two
globular hec&, which are rhe crossbridges between the
thick and thin hlaments of lhe sarcomere The heads of
the healT chains also called 51 fragments-each pos
sessa site for binding acrin as well as a site for binding
and hydrolyzing ATP. The head portion of each myosin
lorms a complex with two light chains, one regulatory
and one alkali. The alkali light chain plays an essential
roLein stabiLizingthe myosin head region. The regulatory
light chain, as irs name implies, regulares rhe ATpase
acti\.ity o[ myosin. The activity of the myosin regulatory
light chain is in rum reguiared via phosphorylation by
Ca']* dependentand Ca'z*-independentkinases.
Figure 9 5C summa zes the interaction between a
thin hlament and a single pair of head groups from the
myosin of a thick filament.

In All Three MuscleTypes,An Increasein

[Ca2+],Triggers Contraction By Removingthe
Inhibition of Cross-BridgeCycling

Underlying muscle contracrion is a cycle in which myosin Il heads bind to actin, rhese cross-bridgesbecome
(thin
distorted, and llnally rhe myosin heads detach from actin.
filament)
Energy for ftis cycling comes from the hydrolysis of ATP.
However, if unregulated,the cyciing would continue until
Myosin(thick ihe myocyte was depleted of ATP. It is not surpdsing,
filament)
rhen, that skeletal,cardiac, and smooth muscLeeach have
headbound
lvlyosin
mechanisms for regulating cross-bridge cycling. In ail
to actinfilamentat
myosin
binding
site
Lhreecell lypes, an increasein [Ca,+]i initiates and allows
cross-bridge
cycling to continue. During this excitatory
FICURE 9 5. Sructure ol ihin and rhick filalrtrls.
increase, [Ca2*1,may rise lrom irs resling level of less
than 10-7 M to greater than l0-5 M. The subsequent
decreasein [Ca2*], is the signaL ro cease cross-bridge
filanents that shadow the acrin double heLix. The lengrh
cycling and relax.
of a single tropomyosin molecule corresponds to about
Regardlessof the muscle r1.pe,Ca,+ moduiates conlracseven actin monomers (i.e., a half tum of the actin helix).
tion through regulatory proteins rather than interacting
A . w e s h a l ls e el a r e r .L h er o l e o f L r o p o m l o - s t o . n l e r - directly with the contractile proteins. ln the absenceof
fere with the binding of myosin to actin.
Ca2t, these regulatory proteins act in concert to inhibit
Troponin is a heterotrimer consisting of troponin T
actin myosin interactions, rhus inhibiting the contractile
(which binds to a single molecule of rropomyosin), tropoprocess.When Ca'?*binds to one or more of rhese pronin C (which binds Ca']*), and rroponin I (which binds to
reins, a conformational change takes place in the regulaactin and inhibits contraction). Troponin C is closely retory complex that releasesthe inhibition of contraction.
lated lo another Ca2t-bincling protein, calmodulin (CaM;
SKEIETALMUSCLE.The heierotrimedc troponin molep. 102). Thus, each troponin heterotdmer interactswith a
cule contains the key Ca']t-sensiiiveregulator troponin C
single tropomyosir] molecule, whlch in turn interactswith
(Fig. 9-64). Each troponin C moLeculein skeleral mus
seven actin monomers. The tropomn compiex also inter
cle has two high-afftnity Car*-binding sires rhat parriciacts directly with the actin filaments. The coordinated
pate in binding of troponin C to rhe thin fiLament.Caz*
I n r e I . l ( l l o -s t r q r g t r o p o n i n .l r o p o - n y o r l na. r d a t L ' n a l lows actin-myosin interactions to be reguiatedby changes binding to these high affinity siresdoes nor changeduring
muscle activation. Each troponin C molecule in skeletaL
in lCa']*1,.
muscle also has two additional,low-affinity Car*-binding
THICK FILAMENTS.
Like ihin acrin filaments, rhick hlasites. Binding of Ca2* to these lo*affinity sites induces a
ments are poLymers of proteins (see Fig. 9 5B). Thick
conformational change in the troponin complex that has
filaments are bipolar assembliescomposed of multlple
rwo elfects. The f,rst effect is that the C terminus of the

CellularPhysjology
of Skeletal,
Cardiac,and SmoothMuscle/ 9
INITIATION
OF CROSS-BRIDGE
CYCLING
IN SKELETALAND CARDIACI\4USCLE

Tropomyosin
Troponin
comPlex

^ ^2+

\rl

The movementof the tropomyosin

deeper into the actin

unmasksthe mvosin bindins sites.

OF CROSS-BRIDGE
INITIATION
CYCLINGIN SN/]OOTH
MUSCLE

---s\

\!vosin

/)_

^ ^2+

\-v

li

.'r, *

Inactive

AIr

Regulatory
lightchain
Activated
myosin

\)
Calmodulin

FIGURE9-6.

Act ve calmodulin/
MLCKcomplex

The role ol Car in triggerLngmuscle contraction MLCK. m),osirl light chain kinase

inhrbitory troponin I moves awa)' lrom the actin/tropomyL r - l r F / T . n t . t h , r .\ r - e | r ' t t i n g . h e r o o o m l o s i nm o o

cule to rnove. According to one hypothesis, the other
effect, transmitted through troponin T, is to push tropomyosjn away from the myosin bindilrg site on the actin
and into the aclin groo\.e. With the steric hindrance re
*
* n o r e d t h e m 1 o : t nh , . d r . . r b l er o i n t e r d .rrr i h l r t r n d
@ engug"n !ro\s bLidge(yLLlng

(ARDlAc MUSCLE.The regulatory mechanism within

cardiacmuscle is similar to that of skeletalmuscle, alh o u g l -r - o p o n t n\ r o m . , d r c m u s .l e h a , 1 - - , , ' ; , ' * 1 .
d c tv ' l o u - a I t i t a / b r n d ' - gs i . .
sMooTH MUscLE.An entirely different mechanismcont o l c . o . . b r J g c u " r o , e ' i n , n o o t h m J . ! l e H e r ! .a n
increasein lCaz-1,initlates a slow chain of eients thaL

9 / CellularPhysiology
of Skeletal,
Cardiac,and SmoothMuscle

ultimately increasesthe ATPaseactivity of the myosin (see

Fig. 9-68). The first step is the binding of four Ca'?*ions
to calmodulin, which, as we noted earlier, is closely related to troponin C. Next, the Ca2*-CaM complex acti
vates an e.zyme known as myosin light chain kinase
(MLCK), which in turn phosphorylates the regulatory
light chain that is associatedwith the myosin-ll molecule.
Phosphorylationof the light chain alters the conformation
of the myosin head, which greatly increasesits ATPase
acrivity and aLlowsit to interact with actin and act as a
moLecularmotor. Thus, in smooth muscLe,CaM rather
than troponin C is the Ca']+-binding protein responsible
[or tra-.ducing LLe Lontractionrriggering increasesin
[Ca,*],. Note rhat in smooth muscle, contraction cannol
begin until MLCK increasesthe ATPase activity of myosin, which is a time-consuming process. In skeLetaland
cardiac muscle, on the othr hand, the ATPaseactivity of
rhe myosin head is constitutively high, and cross-bridge
cycling can begin as soon as the tropomyosin is moved
out of the way.
The mechanism just outlined acrivaresrhe thich frIaments in smooth muscle. Other mechanismsact on the
rhin filaments of smooth muscle to remove the tonic
inhibition ro actin-myosin interactions that are causedby
steric hlndrance. Two proteins-caldesmon and callnhibit the interaction between actin
oonin-tonically
and myosin. Both are Ca2*-CaM-binding proteins, and
both bind to actin and tropomyosin. Calponin, which is
{ound in a fixed stoichiometry with tropomyosin and actrn (one calPomn-one tropomyosln-seven acun monomers), tonically inhibits the ATPaseactivity of myosin. As
we saw earlier, the increasein [Ca'?*],that triggerssmooth
muscle contraction activatesCa2+-CaM.Besidesactivating
MLCK, this Ca'?*CaM complex has two effects on calponin. First, Cd+ -CaM binds to calponin. Second, Ca2*CaM activates Ca'z+-CaM dependent protein kinase,
which phosphorylates calponin. Both effects reduce calponin's inhibition of myosin's ATPase activity. Like caloonin. caldesmon also tonically inhibits the ATPaseactivity of myosin in smooth muscle.

Cycle,Contractile
Duringthe Cross-Bridge
Convert
the
Energy
of ATP
Proteins
Into
Mechanical
Energy
Hydrolysis
The cross-bridgecycle that we introduced in the previous
r e l L ' o r o c l u - s r n f i v es L e p s( F ' g o T l n i r i a l l yr. h e m y o
sin head is attached to an actin filament after the "power
stroke" from the previous cycle and after the actomyosin
complex has released adenosine diphosphate (ADP). ln
the absenceof ATP, the system could remain in this rigid
state for an indefinitely long period, as is indeed the case
in dgor mortis. In this dgid state, rhe myosin head is at a
45-degree angle with respect to the actin and myosln
filaments.
Slep l: ATP binding ATP bindingto the headof the
myosin hear'rychain (MHC) reducesthe affinity of myosin for actin, causing the myosin head to releasefrom
the actin filament. lf ali cross-bridgesin a muscle were
l n r h i >r t a r e .l h e m u s ( l er u o u l db e f u i 1 r e l a x e d .
Step 2: ATP hydrolysis. The breakdown of ATP to ADP

and inorganic phosphate (P,) occurs on the myosin

head; the products of hydrolysis are retained on the
m ) o s i n . A c a r e s - l t o l h l d r o ) y s . s t. h e r r y o s r n h e a d
pivots around the hinge into a "cocked" position (perpendicular or at a 9O-degreeangle to the thick and
thin 6laments).This roiarion causesrhe tip of the myo
sin to move about ll nm along the actin filament so
i l _ a l r t n o l a l i n e s u p w t h a n e w a c t i r m o n o - r e -t \ o
monomers further along the actin hlament (see the box
r r l e d V e a . u r r n gr h e F o r c e o ' a 5 . - g l e C r o > , - B r i d g e
\ )\,(,

v ,r(

daarLi.

rr

--hridop-

in

m r r < ,l p

were in this state, the muscLewouLd be fully relaxed.

Step 3; Cross-bridge formation. The cocked myosin
head now binds to its new position on the actin frlan e n l . l h i s b r n d r n gr e f l e c t t<h e r n . r e a s e a
df f n i t ; o l t \ e
myosin-ADP-P,complex for actin
Step 4: Release of P, from the myosin. Dlssociationof P,
frnm

rhe

mtn.rn

he,rl rriooer- rhe nnrver crrnLe

conformationaL change in which the myosin head

bends approximateLy45 degreesabout the hinge and
pulls rhe acrin ament about ll nm toward the tail of
rhe myosin nole.ule. lhrs Lonformarionalchange
causesthe aclin filament to be drawn aLongthe myosin
fiLament,thereby generatingforce and motion.
Step 5: ADP release. Dissociation of ADP from myosin
completesthe cycle, and the actomyosincomplex is left
in a rigid state. The myosin head remains in the same
position and at a 45-degree angle with respect to the
thick and thin filaments. The ADP-free myosin complex remains bound to actin until another ATP binds
en/'l ,n,ri,rp< rnnthpr

r.rlp

The ADP-free myosin complex ("attachedstate" in Fig.

9-7) would quickly bind ATP at the concentrations of
ATP normally found within cells. lf unrestrained, this
c;.1rng
rros,-bridSe
c o n t r n r e r n l 1 d e p l e L i r gL h e
"ould
cytoplasm of ATP. At that time, the muscle would remain
in the stiff "attached state" becausereleaseof the crossbndge, Irom actin -equiresbinding of AIP o m)osrn.
Ac dis.ussedearlier.musclecells do not egularecroc<bridge cycling by modifleng lATPl,. lnstead, skeletalmuscLeand cardiac muscle control this cycle at the third step
by preventing cross-bridgeformation until the tropomyosin moves out of the way in response to an increasein
lCa'?*],.Smooth muscle controls the cycle at the second
step by prcventing ATP hydrolysis until the ATPaseactivity of the myosin head increasesin response to an increasein lCa'z*1,.
Although this general schema of cross-bridge cycling
occurs in smooth muscle as well as skeletaLand cardiac
muscle, the frequency of cross-bddge cycling in smooth
muscle is less than one tenth the frequency encountered
in skeletal muscle. This variation reflecm differencesin
the propeflies of the various myosin isoforms that are
expressedin various ceLl t1pes. Even though cross-bridge
cycling occurs less frequently in smooth muscle, force
generation may be as great or greater, perhaps because
the cross-bridgesremain lntact for a longer period with
earh Lycle lL .s l-kelv rhat thrs longer oenod during
whlch the cross bridges are intact reflects a lower rate of
ADP releasefrom the smooth muscle isoform of myosin.

CellulafPhysiology
of Skeletal,
Cardiac,and SmoorhMuscle/ 9

ATTACHEDSTATE
Actin(thinfilament)

Pl

Myosin(thickfilament)

gl-,
I ADPis released.
]
POWER-STROKE
STATE

RELEASED
STATE

P is released.Myosin headschange
conformatron, resulting in the power
.troke.The filaments5lidepasLeacholher.
ATP is hydrolyzed, causing
myosin heads to return to
their resting conformation.

COCKEDSTATE

FICURE 9 /. The cross-bridgecycle in skeletal and cardiac muscle Each cycle advancesthe myosin head by rwo acrin monomers, or approximaiely
1l nm.

BecauseATP StoresAre Small.the Cell

Must Regeneratethe ATP Needed For
Muscle Contraction

In comparison wlth the energy stored as phosphocrea,

tine, glycogen is a far more abundant energy source
within skeletalmuscle. Glycogen that has been previously
stored by muscle can be enzl.rnaticallydegraded to pyruEach cross-bridgecycle consumes one moLeculeof ATP.
vic acid. Degradationof gLycogento pyruvate is rapid and
ln skeletal muscle. the entire cellular store of ATP is
liberates energy that the cel1 lnvests ln phosphoryLating
sufficient to aLlowonly a few secondsof continuous maxADP to rreld ATP. Pyruva.ecan be furthe deg'aded
imal contraction. Therefore, the muscie cell must reslnalong with other foodstuffsby axidat:e metabolism,which
thesizeATP from ADP at a rate comparableto the rate of
over the long term is the primary mechanism for the
ATP consumption. Skeletalmuscle has specializedenergy
regenerationof ATP (p. 1220). The rate of ATP generaslores that permit rapld regenerationof ATP. The mosr
tion by oxidative metabolism is limited by the rate of
r e a q i l va v e . l a b l ep o o l o f r h i s e n e - g ) r > L L e h i g h - e n e r g y oxygen delivery to the rnuscle.However, glycolytlc formaphospharebond of phosphocreatine. The enz)rmecreatine tion of pyruvate occurs independently o[ oxygen, as does
phosphotransJerae
transfers the high-energy phosphate of
the conversion of pyruvate to lactate. Ihis anaerobicme
phosphocreatineto ADP, thereby rephosphorylatingADP
tqbolsm of muscle glycogen ensuresthat energy stores are
to ATP. The phosphocreatineconient of skeletalmuscle is
sufficient to sustain muscle activity for nearLya minute
adequateto repLenishthe ATP pool severaltimes, but it is
even when oxygen is unavailable.in Chapter-59 we will
s t i l l r n a d e q u a tfeo - . r . r a - g r h e e n e r g ) n e e d ' o . o n discuss the aerobic and anaerobic metabolism of exercistractins muscle for more than 10 seconds.
ing muscle in more depth.

Cardiac,and SmoothMuscle
of Skeletal,
9 / CellularPhysiology
A

SKELETALMUSCLE

Myofibril
Plasma
membrane
(sarcolemma)

reticulum
cisterna
Sarcomere

lnvaginations
of plasma
membrane
(formlrans-

Transverse
tuoute
Sarcoplasmic
reticulum
crsterna

versetubules)

FTCURE9 B. PLrsma-mmbrae invaginarions A, The rransvcrserubules (T Lubules)are exiensions ol the plasma membrane, penetrating the muscle
cell ar t\Vo points in each sarcomere: lhe iunctions ol the A and I bands. B, Smooth muscle cells have rudimentary in\'aginations of dre plasma
membrane. callectcaveoli, contacting wrth rhe sarcoplasmicrclicuium

COUPLING
EXCITATION-CONTRACTION
ln our discussion of the mechanism o[ muscle contractron, we saw that regardlessof whether the muscle is
skeletal, cardiac, or smoolh, it is an increase in [Ca']*],
thar rriggels muscle contraction. The iime during which
[Ca'?r'],remains elevateddelermines the duration of muscle contraction. The processby which "excitation" triSgers
the increase in lCa'z-l' is known as excitationcontracLion
coupling. Diflerent kinds of myocytes have specialized
mechar.iismsthat regulate lhe entry of Ca2+rnlo the cylo
plasm, as rvelL as remove Ca2t lrom the cytoplasm once
the stimulus 1br muscle contraction subsides. Caz- can
enter the cytoplasm from the extracellular space through
voltage-gated or ligand-gated ion channels, or alternatively, Ca'z* can be releasedinto the cltoplasm from the
SR. Thus, both extracellularand intracelLularsoulces conLdbure to the ir.rcreasein lCa']*],. Hor,veYer,the relative
importance of these [wo sourcesva es among the differ
enl muscLelypes.

Invaginationsof the SarcolemmaFacilitate

Communication Between the Surfaceof the
Cell and lts Interior
The plasma membranes of muscle cells display invaginations ihat extend the surface membrane into lhe muscle
ce1L.In skeLetaland cardiac muscle, these invaginations
rake the form of radlalLy projecting tubes ca]led transverse tubules or T tubules (Fig. 9-BA). T tubules are
highly organized and penetrate the muscle at two points
in each sarcomete:al the junctions of the A and I bands.
A cross section through the A-l junction would show a
complex, branching array of T tubules penetrating to the
center of the muscie cell and surrounding the individual
myohbrils. Along its Lengthlhe iubule associateswilh two
cistemae, which are specializedregions of the SR. The
sarcoplasmic reticulum is the muscle equivalent of the
endoplasmic reticulum, and it serves as a storage orga
T h e . o m b i n a t r o no r t h .
n e , l e l o r u r t r a . e l l u l r rc a
T-tubule membrane and lts two nelghboring cistemae is
called a triad: Lhis struclure plavs a cruciaL role in the

CellularPhysiology
of Skeletal,
Cafdiac,and SmoothMuscle/ 9

241

Membrane depolarization opens

the L-type Ca'- channel.
Mechanical coalpling between
the L-type Ca'- channel and the
Ca'--release channel causes the
Ca2+-releasechannel to open.

channel(ryanodine

receptor)
[tetramer]
Ca'- entering the cell via L-type
Ca'- charurelsalsocan activate
the Ca2"-release
channels.
However, this pathway is not
essential in skeletal muscle.

ca2* eits thisR via the

Ca2+-release
channeland
activates troponin C, leading
to musclecontraction,

L-typeca2* \r
^h.nnal

ca2*

/nHo

T-fi'hr rla

receptor)
[inarraysof 4]

r
J ca2'
ca2* Mechanical
connectton
SRterminalcisterna

FICURE 9- 9. Excitation contraction coupling in skeletal muscle

retrad ot four L lype Ca:* channels on the T tubules facesa single Ca2*-release
_A
chamel ofthe SR, so that each L type Ca':* channel inreracts\!ith lhe Ioor of one olihe four subumts of rhe Ca, -releasechannel. N;!e
thar half of
rhe car*-releasechannelslack associarionswith L-rype caz' channels DHp, dihydroplridine; sR, sarcoplasmicrrjculum

coupiing of excitation ro contraction in skeleLaland cardiac muscle. Smoothmuscle, in contrast, has more rudimentary and shaLlowinvaginationscalled caveoli (seeFig.
o_ B8).

In SkeletalMuscle, Depolarizationof the

T-Tubule Membrane Leadsto Ca2*Release
from the SarcoplasmicReticulumat the Triad
Action potentials originaring ftom depolarizationsat the
motor end plate propagate along the skeletal muscle
membrane and down the T tubules. DepolarizationoI the
triad region of the T tubules activatesL-type Ca2* channels rp. lo0'. whi.h are ,l-:tered 'n q oup: ol lou. a l l e d r e r r a d cr F g o - o r I h e , e r o l . a g e - g a r et ld- , n n e l ,
play a pivotal role in coupling electrical excitation to
contraction becausethey function as the voltage sensor
i n r C c o u p l i n g .E l e c r r o nr c r o . c o p ) r e v e a l s, . h e . [ e board pattern of projections arising from the T tubule
membrane and extending toward the cisternaeof the SR;
these projections probably represent the cytoplasmic face
oI these L-t1pe Ca']* channels. Each oI rhe four voltagegared Ca cha nel" in a reLradrs - lacr a reteropenia-

meric protein (see Fig. 7 12B). Each of the lour Car*

channels is also called a DHP receptor, because it is
inhibited by a class of antih)?ertensive drugs knowl as
dihydropy-ridines.Depolarization of rhe T rubule membrane evokes conformationaLchangesin each of the four
L-t1pe Ca'?t channels and has two effects.First, lhe conformational changesallow Ca2* to enter through the four
channel pores. Second, and much more important, the
conformational changesin the four L-type Ca2t channels
incluce a conformational change in each of the lour sub
unirs of another channel-the Ca2*-releasechannelthat is located in the SR membrane
The Ca2*-release channel (Table 6-2, #18) has a
homotetramedc structure quite dillerenr from thar of the
L-tl?e Ca'z+channel that constitutes the voltage sensor.
The Ca2*-releasechannel in the SR is aLsoknown as the
ryanodine receptor becauseir is inhibited by a class of
drugs that include the planr alkaloids ryanodineand cat'Jeine. Ca2*-releasechannels cluster in the portion of the
SR membrane thar faces the T tubules. Each of the four
subumts o[ these channeLshas a Largeextension-also
known as a "foot." These feet projecr as a regular array
into rhe cytosol. The foot of each of the four Caz*-release

9 / CellularPhysiologyof Skeletal,Cardiac,and Smooth Muscle

channeL subunits is complementary to the cltoplasmic

proleclion of one of the four L-type Ca2* channels in a
i e r r a oo n t h e T t - : b u l e' ' e e F 8 . o q r f h e c l o < ep n r s c a l
proximity of these two proteins, as well as rhe ability of
6oth DHP and ryanodine to block muscle contraction,
suggeststhat inLeractlonbelween these two different Ca']+
channels underlies EC coupling. The precise mechanism
of interaction between these Proteins is not yet fully understood, although we know that it is not electrical inasmuch as ion conductance of the Ca'z--releasechannel is
not strongly voitage dependent. A large cytoplasmic projecrion on the ar subunit of the L-type Ca'z* channel
ippeats to be necessaryfor interaction between the lwo
Cd* channels on opposing T-tubule and SR membranes
Thus, it is possible that direct mechanicalcoupling exists
channel
between this projection and the Ca2*-release
As the L tlpe Ca'z* channel on the T-tubule membrane
mechanically opens the Ca2+-releasechannel in the SR,
Caz+ sequesleredin the SR rapidly ieavesvia the Ca']+
release channel. The resultant rapid increase in [Caz*]t
activales troponin C, thus inilialing cross-bridgecycling
as described earlier. The entire Process,extending from
depoladzation of the T-tubule membmne to the initiation
of cross-bridge cycling, is lermed excitation-contraction
couplinq.
ol tre Car"-reA , r n o i g hw e n a ' e . t r e ' , e d a c l i \ a t i o n
coupling
between it
leasechannel in the SR by mechanical
membrane,
in
the
T-tubule
Ca2*
channeL
L-t1pe
and the
local elevations in lCa']*]r can also aclivate the Caz*-release channel in skeletaLmuscle. When the L-t)?e Ca']+
channel opens during depolarization, it al1owsan influx
of Ca2* that locally increases[Ca'z*]'.This mechanism of
activating the Ca2*-releasechannel in the SR is known as
Ca2*-induced Ca2* release (CICR). Although L-tpe
Ca2* channels allow lCa"]r lo rise during action polentials in skeletalmuscle, CICR is nol necessaryfor conlraction. Indeed, skeLetal muscle conlraction persists even
when Ca2* is absent from the extracellular fluid. However, as we will see later, CICR plays a critical role in EC
coupling in cardiacmuscle.

Ca'?* channels, the contribution of CiCR to the rise in

[Ca'z*],ls greater than the flux contributed by the Ltype
Ca2* channelsof the T tubules.
It appearsthat each L-type Ca2* channel controls only
one SR Ca2*-releasechannel. The close physical proximity
of L{}?e Ca2* channels of the T-tubule rnembrane and
the Caz*-releasechannel in the SR at the lriad junctions
aLlowsfor this tight local control. Although Ca'* diffuses
in the cytosol away from its SR releasesite, Ca2* release
at one site does not appear to be able to induce Ca2*
releasefrom a neighboring SR Ca2*-releasechannel.Thus,
Ca2- releaseevents are not proPagaledalong the myocyte.
ln fact, the SR Cazt-releasechannel does not appear to
- e s p o r dt o g e - e r a 1 , z ei d
n c r e a - e si n ( ) l o p l a s m i cl L a 2 I
Generalizedcardiac muscle contractions occur as a result
of the spatial and temporal summation of individual CICR
evenls-

In Smooth Muscle,Both Extracellularand

lntracellularCa2*Activate Contraction
In smooth muscle cells, three major pathways-which
are not mutuaily exclusive-can lead to the increasein
l L a ' I L n a ll r . 8 8 e r sc o ' l t a c l i o n :I I ' C a e r t r v l h r o u g h
voltage-gatedchannels in responseto celL depolarization,
( J l C a z e n t r yt l ^ r o u g h
! 2 1 C a ' r e l e a , el r o m t h e S R .a n d
channels.
voltage-independent
As
CIIANNELS.
Ca'?*ENTRYTHROUGiIVOLTAGE-GATED
noted earlier, smooth muscle cells respond to stimulation
with graded depolarizationsor action potentiais. In either
case, depolarization may produce an influx of Ca'?*
through voltage-gatedL-t1pe Ca2* channels(Fig. 9 l0)

FROMTHESR.This ca2* releasemay occur

ca,, RELEASE
by either of two mechanisms:CICR or IP3 mediated Ca']*
release.As we have already seen, CICR plays a key role in
EC coupling in cardiac muscle, where the L-type Ca'z*
channels are highLy ordered and in close proximity to the
Ca2* release channels in the SR. Thus, Ca2* influx
through L tlpe Ca2* channels can triSSer CICR ln
smoolh muscle, the relationship between the plasma
and the SR is not as regularly organized as it
In CardiacMuscle,Ca2*EntryThroughL-Type membrane
is in striated muscle- Nevertheless,eleciron-dense couCa2*Channelsls AmplifiedBy Ca2*-lnduced plings have been observedbndging the B- lo 10-nm gap
from the Sarcoplasmic
Ca2*Release
between the cel1 membranes and elements of the SR in
Reticulum
smooth muscle. Although CICR occurs in smooth muscle
cells under some conditions, it requires [Ca'?*],levels that
not
require
muscle
does
Whereas EC coupLingin skeletaL
conare higher than those that typically occur under physiocardiac
L-t)?e
Ca'?n
channels,
through
influx
Ca2*
logical conditions, and its role remains unclear.
traction has an absolute requvement for Ca2* influx
A more important mechanism for Caz* releasefrom the
through these channels during the action potential. Beof smooth muscle is the lP. pathway. The existenceof
extracelSR
cause the T-tubule Lumenis an exLensionof the
pathway is supported by the obsewation that some
this
from
bulk
diffusion
of
Ca2*
facilitates
the
lular space, ir
agonistscan elicit smooth muscle conlraction
extracellular
Ca'?*
channeLs
of
the
L-type
fluid
to
the
site
e"trace11uLa,
with minimal depoladzalion and negliglble Ca2+ influx
on the T-tubule membrane. Thus, the Ca2* can simuha
neously reach superficial and deep regions of the muscLe. Furthermore, even for agonists such as serotonin or nor
epinephrine, which activate a Ca']*-influx pathway, ihe
The increasein lCa'z*],resulting from Ca2* influx alone is
obser.redincreasein [Ca'?*j,is out of proportion to that
not, however, sufftcient to initiate contraclion. Rather, the
expected from Ca2* influx alone. Thus, another pathway
lncrease in lCa']+lr that is produced by the L tlpe Ca'z*
must exisL for increasing lCa2*1,. Some agonisls cause
channelsis greatly amplified by CICR from the SR via the
smooth muscle contraction by triggering the production
Ca2*-release
lndeed,
because
the
Ca2*-releasechannels.
L{ype
of lP, (p. 100), which binds to a specific receptor on the
period
than
do
for
a
longer
remain
open
channels

CellularPhysiology
of Skeletal,
Cardiac,and SmoothMuscle/ 9

MALIGNANT HYPERTHERMIA
lvlalignanthyperthermia(MH) is a geneticdisorderaffecting betweenI in 10,000and 1 in 50,000 individuals.
Affected individualsare at riskfor a potentially life-threatening syndromewhen exposedto any of the various
inhalationanesthetjcagents,particularly
halothane.Administrationof succinylcholine
can alsotriggeror exaggerateMH. This drug is a short-actinginotropic(nicotinic) acetylcholine-receptor
antagonistthat acts by first
receptorchanneland then
openingthe acetylcholine
blocking it, thereby resultingin a burst of muscleactivit,
followed by paralysis.Onset of the syndrome in the setting of the operating room is typified by the development of tachypnea(rapidbreathing),low plasma[Or],
high plasma[COr], tachycardia(rapid heart rate), and
hypefthermia(tising body temperature),as well as rigidit,
sweating,and dramaticswingsin blood pressure.
The
.i'C
patient's temperaturemay rise as rapidly as
every 5
minutes.The onsetof MH is usuallyduring anesthesia,
but it can occur up to severalhours later. lf untreated,
the patient will develop respiratoryand lactic acidosis,
muscularrigidity,and a breakdownof muscletissuethat
leadsto the releaseof K* and thus profound hyperkalemia. Theseepisodesrefiect a progressivelyseverehypermetabolicstatein the muscletissues.Fortunatelv,
our
evolvingundersl.anding
ot the physiologyol MH hasled
to the developmentof a therapeuiicregimenthat has
greatlyimprovedLheonce-dismal
prognosis.
The majorfeaturesof the syndrome-hyperthermia,
muscularrigidity,and an increasedmetabolicrate-led
early investigatorsto suggestthat MH was a diseaseof
abnormalregulationof musclecontraction.Accordingto
uncontrolledmusclecontraction-somethis hypothesis,
how triggeredby the administration
of halothaneand
succinylcholine-causes
excessive
adenosinetriphosphate
(ATP)hydrolysisto provide energyfor contraction.The
increasedrate of ATP hydrolysisleadsto an increased
metabolicrate as muscletriesto replenishand sustainits
ATP stores.Hyperthermiadevelopsbecauseof the heat
liberatedby the hydrolysisof ATP.
Furthersupportfor this hypothesiscamefrom the observationthat more tension developedin musclefibers
obtainedby biopsyfrom susceptible
individuals
than in
when the fiberswere exfibersfrom normalindividuals
posedto halothane.In musclefibersfrom both humans
and a strainof swinesusceptible
to MH, Ca,+-induced
from the sarcoplasmic
retjculum(SR)is enCa2*release
hancedwhen compared with fibers from unaffectedsubjects. Furthermore,caffeine,which causesthe Ca2n-releasechannelsto open, inducedgreatercontractions
in
fibers from susceptiblesubiects.Takentogether, these
suggestedthe possibility
observations
that MH results
from an abnormalityin the Ca,+-release
channelin the
SRmembrane.
In both humansand animals,inheritanceof MH fol-

membrane of the smooth muscle SR (p. 100). This lP.

- e !e p L o < r l 5 ,l f a . r g a d - g d t e d C d
! ranne.. fhu<. a
receptor in the plasma membrane can indirectly induce
La
rel<lt, lrom t\c 5R anq hence conLra.Lron.
Ca2* ENTRY THROUGH VOLTAGE-rNDfPff\rDfwr CHANNELS. ln smooth muscle it is possibLe that extraceLlular

pattern.Cloning
lows a mendelianautosomal-dominant
of the gene (RyRl)encodingthe Ca2*-release
channel
(ryanodine receptor)allowed genetic linkage analysisto
demonstratethat human MH is closelylinkedin some
familiesto the RyRlgene on chromosome19. In swine,
MH resultsfrom a singleamino-acidsubstitutionin RyRl
(Cysfor Arg at position 614). An analogoussubstitution
is presentin some human kindredsas well. Thissubstitution increasesthe probability that the Ca2*-release
channel will be open. In other families,MH hasbeenassociated with other geneticabnormalities
in the RyRI gene.
In still others,MH does not appearto be genetically
linked to the RyRl gene. lt is possiblethat defectsin
other stepsalong the excitation-contractioncascadecan
resultin abnormalregulationof musclecontractionand
the MH phenotype.Forexample,when under anesthesia,
patientswith some forms of musculardystrophy may
have metaboliccrisesthat resembleMH.
MH also occursin domestic livestock.The incidenceof
MH i5 particularly
high in swine,where episodesare triggered by a variety of physicaland environmentalstresses
(porcinestresssyndrome).MH in animalshassignificant
economic importance in view of the potential lossfrom
fatal episodesand the devaluationof meat as a result of
muscledestructionduring non-fatalepisodes.
ln humans,a conditionsimilarto MH may occur in
patientstreated with neurolepticagenis such as the phenothiazinesor haloperidol.lt is called lhe neurolepticmolignont syndromeand appearsto resultfrom abnormally
high neuronalinput to the musclecells.
Therapyfor MH now involvesadministrationof the
drug dantrolene,cessationof anesthesia,and aggressive
efforts aimed at cooling the body. Dantrolene is an
effectivetherapeuticagent becauseit blocksexcitationcontractioncouplingbetweenT tubulesand the SR,thus
interrupting the otherwise uncontrolled progressionof
muscularcontractions.
The drug can be given acutelyin
an effort to abort an ongoing attack or, in a person
known to be at risk, it can be given before the initiation
of anesthesiain order to prevent onset of ihe syndrome.
Therapyalsoincludesintravenous
hydrationand the judicioususeof diureticsto keepthe urineflowing.The latter
lessensdamage to the kidneysfrom the releaseof breakdown products,suchas myoglobinfrom the damaged
muscles.Sodiumbicarbonateis givento counterthe lactic acidosis,
and patientsmay be mechanically
hyperventilated to blow off the excessCOr.
Despitethe intensiveprotocoljust outlined,MH is still
assoclatedwith high mortality. The relativesof a patient
with a documentedhistoryof one episodeof MH should
be carefullyscreenedto see whether the, too, carry the
inherited trait; many of the affectedrelativesmay demonstratebaselineelevations
in muscleenzymeleveisin their
blood (e.9.,an increasein creatinekinaselevels).

Ligands may rrigger the influx of Caz+ through either

ligand-gated channels (p. 170) or channels that are acti
valed via G-protein-coupled receptors.Nevertheless,it is
noi clear to what extent, if any. these tlpes of Ca']+
c h a n r e l -c o n t r . b u r ct o [ , . a I r c - e a s e si n . . r . o o r h r u , cle. However, another class of channeLs-store-operated
C a ' c h a n n e l s- a p o e a r s t o p l a r a n m p o - t d . l rLo e N e u

9 / CellularPhysiology
of Skeletal,
Cardiac,and SmoothMuscle

Extracellular
space
Voltage-gated
Ca'- channel

ca2*
t

Agonist

Caveolus

/Receprol

)-

,t.a,

I
When the SRCa2+storesbecome
depleted,the SRsignals-by an unknown
mechanism a store-operatedCar+
channelto open,allowing Ca2*to enter.

r...-.'-<Y-

/ e1.,icomprex

/
PhospholipaseC

aj
Sarcoplasmic
reticulum

Ca2*releasefro]ithe sarcoplasmic
reticulun can occur either via
^2+
,
.^2+
.
importantly, via lP3 activation of
SR Ca'- channels.

F|cURE9_l0'EXcitation'.ontraction(EC)corrpIrlgrrrsrrroothmrrsc1eDAG'diacylglyceroLlIP].inosilol]',+'51|iphosphate,
inosiiol ,l,5 biphosphate;SR, sarcoplasmicfericulum

r o . r n s m i r e 5 l L a L e - ( l o r h e d i " ,h a r B-. a n c L h - r n e
depletlon of SR Ca'z- stores (i.e., second pathu'a,v)
somehow lead Lo the activatjon o[ store-operatedCa:*
' -le-ini
. h a n r r e L. n r h e D l . - m J r c n l - a n e l L e , I
through these channels ailor,vslCa']*1,to remarn elevaLed
even after SR depleLionand also appearsto replenish SR
@ Cat' srores.
T o g ,t h , . . L h e > e . u r r dp d l l r r r , j ) 6 1 ' n 1 s 3 ' g [ t a :
'(.r' releJiefo r .l-e 'Rl ard rhc rh.rd pi-t \\.i) ,!2
r n [ . ' , t L u r . B h- t o " - o p e a e d c L .r n , l , h . ' . b , , n . . , 1 1 . .
pharmacomechanical coupling because these excitatory
neurotransmitte$ and hormones can induce smooth mus
cle contraction that is independent of action poLenLial
generation. Regardlessof the source o[ the Ca']*, the resuhant increasein [Ca']t], leads to contraction via a Ca2CaM-dependent increase in MLCK actlvlty and myosin
phosphory-latlon.

amount o[ lorce developedat any gl\'en [Cat-], may vary.

This force/[Ca" l, ratio ].naybe increasedor decreasedand
is generally higher dr-u.ingpharmaconechanicaLactivation
than during depolanzation-activatedcontractions.Because
phosphorylation of the my,osin lighL charn (N4LC) is a
major determinantof contractilelorce in smooth muscle.
! r i n J !J ( n ( l p ' l . o r r J r, r o n r r . J 1 e . u l t e ' l e r [ - o r' r r '
increasein the rate o1 MLC phosphorylatlon by MLCK or
from a decreasein t].rerate of MLC dephosphorylationby
MLC phospl-ratase.
One second messengefsystem that can
is protein kinase C
decreasethe activity of pl.rosphatases
(PKC) (p. 102). Some excltaLorystir.nuli are therelore capable oI initlatlng smooth muscle contraclion by induclng
IPr-mediated releaseoI Ca2t from intraceLLuLar
stores, as
rvell as by producing PKC-mediated decreasesin MLC
Tre
; h o s p L t t " ' er c t t \ . L y l L e 5 ep a t | , . t . r , . . f u t t L e t. r ; m p l c of pharmacomechanicalcouphng.

Smooth MuscleContractionMay Also Occur

Independentlyof Increases
in [Ca,*],

TERMINATINGCONTRACTION

\ \ h e r e a , - n "r ) e \ , r d r o) - r . r r - l i r e l ) o n r r . , ( < e [Ca2'],to evokeconlraction,somestimuli appearto causc

conlraction withoul a neasurable increasein [Ca']*],. One
m e . h d n . c r Tbtv i l L ' , h e r . . t " r t o 1 ' L i r u l i - r g \ r . n d L r . ,
r a 2 - . n d e p e n d e. ror t, t r " . . i o n r, . b , r ' o d u : r - g t t r er . t r

In Skeletal,Cardiac,and Smooth Muscle,

Terminating Contraction RequiresRe-Uptake
of Ca2*Into the SarcoplasmicReticulum

,,' n{. nnrart lp nr rcorrl,ron nrn,nin-rli'.rlr

lh,

rnp

After the contracrion-activating stimulus has subsiclecl,

Ca2' must be ren1ovedfrom the c1'toplasmfor contrac-

Physiology
of Skeletal,
Cardiac,
andSmoothMuscle/ 9
Cellular

Nd-Cd dnd e\Lhdnge'dnd Ca/ pump in the

piasma membrane both extrude Ca:+ ftom the cell.

ticulin is a ubiquitous Ca:- bincllng protein that is found

in r--i.rrlrrr hi.h ,, n.. l.r'ron)w-t '- thc 5R o[
- - r o o t hr u * e . l h e - cp r o r c , r h
- r . e , t r " n e r d o r. , a l r . i . 1 r o b r n d t a 2 ' ' r i t h u p t o 5 0 h i n d r n g- \ p e r p - o r e - r
molecule.
Ca'z' binding proteins are not located diflusely within
rLe sR

'r\ ( .,

Ca2+is bound in the

sarcoplasmicreticulum by
caheticulinand calsequestrin.

Calreticulin
\

.=It

Ll"/

ll_.,::...
t't
1,:
|

(_t

',

Calsequestrin/

9 11. Mechanisms
ol Ca: removal liom Lhc cytqrhsm.
FICURE

tion lo ceaseand for relaxation Lo occur. Ca2t ma1' be

extrudecl across the cell membrane or sequesteredwitl-rin
in

r,pl-r-:,^r

Rr her

rrl.pn ip.rf.

i. h ofl.

l,,c,l :pd ro thp

region ol the SR rmmediateLybeneath the triad junction.

Calsequestrinappearsto bind directly at the triad, where
r f, n<
.nnn, ' r. rh h" a
r e l e a , .. h r n n e l a n wirh two orher Lrlad proteins, juncrin and rriadin. Here,
calsecluestrinis poised not only to aid n.rusclerelaxation
by bultering Ca']' n'ithin the SR lumen but also to unload

Ca2*pump sequesters
Ca2+within the
sarcoplasmicreticulum.

Sarcoplasmic
reticulum

245

)r rFrF-\fFro

o-ll)

r - r B c r t h e r, n \ ' - C " e x
lhe .cll na1 r{tr rd Ca
changer (NCX, p. 68) or a Cart pump at the plasma
membrane (PMCA, p. 64). Extrusion acrossrhe cell mem
brane, however.,rvould eventually deplete the cell of Ca:'
and is tl-rereforea minor mechanism for Ca2- removal
from the cytoplasm. lnstead, Ca2* re uptake into the SR
is the most important mechanism by r,".hich
o r p 5 rl g l c \ e . . r J
rq-.rplal(
r . ,ell rc-rn- (e2
by the SR is mediated by a SERCA-type Ca2- pump
(p.64).
It rs possible that the rate of Ca']= re rqrtake into Lhe
SR may be regulated by modulating ihe activity of the SR
r , ' . r - r a l . - e y r n n p I n . r , l r J . m u . c l e .S R ( : ,
l u m p a c l i r ,) r - r r b r e d b v t h e r e g ud L ^ n p f o t e p h o s pholamban. When phospholambanis phosphorylaLedby
cyclic adenosinemonophosphate (cAMP) dependenLprotein kinase (PKA), its ability to inhibit the SR Caz' punp
Ls lost. Thus, activatols of PKA, such as the neurotransr ' ' r ' l . e p e p h r r e r r a r c n a r c e L h et a L eo [ c a d i . - ' .l y ocyterelaxation(p. 525).
SR Ca']*pump acti\ity is also inhjbjLedby high lCa':-l
\ \ r l l L l r (\ R l u n - . n . l h . s
brion of )R Lr/ -DUnl
activity is clelayeclby Ca']' bindrng proteins u'iLhin LheSR
' l u rr r r . l h e s . r r b d i n g p - o t e . n1. ' L r l l et hr e t . r
in
tl.re
SR
during
Ca']
re
uptake
and
thus
markcrease
edLy increasethe Ca']t capacity of the SR. The principal
- [ ( ( 1 2 n ] - c e . c a l : e q u e s t r i n .Cr o' d nB pror r
also present ln carcliacand some smooth muscle. Calre-

1 rhp . , rri '

nJ rhp , 17--cl,a,e .hl-rel

and

thus facilitate EC coupling. lt has been hypothesizedthat

b ( . o . f t t P r o n o t e s( r ' r e e r ) P - o n ( a l ) e q J e ) t r ' - .
making Ca:- availablefor exit from the SR.

In Smooth Muscle,Terminating
Contraction Also Requires
Dephosphorylationof the
Myosin Light Chain
BecauseCar- Lriggerssmooth niuscle contraction by inducing phosphoq'lalion ol the myosin regulatory 11ght
. n d i r ' ' r e e ) e - L n r t [ r a - I r o - l o \ \ - e > L r n \gd l L r e
ma)' not allor,v muscle relaxatlon. Rather, relaxation of
smooth muscle requlresMLC dephosphorylaLion,which rs
accomplished by myosin Iight chain phosphatase. This
phosphataseis a heterotrimer consisting ol subunits with
molecularmassesof 130, 20, and 37 kDa. The 130-kDa
subunit confers specilicity by binding to myosin, whereas
, . o r er r - r L ec r r ; 1 1 r r. ', r b u r r r- e r p o- . b l c o . l ^ ej 7 - 1 , D p
dephosphorylating
acriliti'.
the

REGULATINGMUSCLECONTRACTION
MuscleContractionsProduceForceand/or
Shortening and, in the Extreme,Can Be
StudiedUnder Eitherlsometricor lsotonic
Conditions
The total lorce generatedby a muscle is the sum of the
b c e . e e r . r . t e Jh ; . r " n 1 r n d c p . n Jn,r l ; , 1 . 1 g a . i myosin cross bridges. The number of simultaneouslycy( . g , r o * - h r J g ( ' d " p e r d s - u b - r .r t , . r l 1 1
on the
tra
lengLh of tl.re rnllscle hber and on the pattern or [requency of muscle cell stimulation. When muscle is stimul a r e . lt o . o n t r a . . . i . e x e r ' >d b r c e . e l q r r ' g r o p u t l l . r e
athchment points at either end toward each other.
This force is referred to as the tension developedby the
muscLe.
Two mechanical and artificial- arrangementscan be
used to study muscle contraction. In one, the attachment
points are immobile, thereb,v fixing the uiuscle lenglh.
Here, stinulation causes an increase in tension, but no
shortening. Becausethese contractlons occur at constant
ier-rgth,they are relerred io as isometric contractions
'T'g o- 2ql
th, -r.onJrringe rrnl. o ol thet,ro
"
attachmenL noints is n.Lobile.and a force or load-

46

9 / CellularPhysiology
of Skeletal,
Cardiac,and smooth Muscle
c

ISOMETRIC

LENGTH-TENSTONDIAGRAI\,I(ISOMETBIC)

.100
Total
75
,--

Muscleflber. ..-

Tension 50

Actrve

Passive

t
100 115
Lengrn

Tension
low

Tension
high

1 3 0 145

D "ACTIVE'LENGTH.TENSION
DIAGRAM(ISOMETBIC)

ISOTONIC

(ISOTONTC)
D AGBAr\,1
E LOAD-VELOCTTY
The maximal velocity
is ihe sameai all lhrce
initial musclelengths.

Velocityol sotonicconiraclon at 3
dlfferentin t a restrg lenglhs

F|CURE912.1sone|ricandisoton1.cLrnrraction'l']-4crrm.n1aLPrep'lron1!)|

\elocit-r of mlrsc[_
qrcefer tnsLolltnar can r snortef nu:cLe.

of SLeletal,
Cdrdiac,and SmoolhMuscle/ 9
CellularPhysiology

MEASURING
THEFORCE
OFA SINGLECNOSS-BRIDGE
CYCLE
The force of a single cross-bridgecycle has been measuggeststhat the quantal displacementof a single crosssured directly. Finer,Simmons,and Spudichused optlcal
bridge cycle is approximately l1 nm. When the tweezers
tweezers to manipulatea single actin filament and place applied a force sufficientlylarge to immobilize the actin
it in proximity to a myosin moleculeimmobilized on a
filament, the investigatorsobservedstepiike impulsesof
mibead (Fig.9-13). With the useof video-enhanced
force that averagedaround 5 pN. This observation,made
croscopythese investigatorswere able to detect moveunder "microscopicallyisometric" conditions,suggests
mentsof the actinfilamentas smallas 1 nm. The oDtical that the quantal force developedduring a single crosstweezerscould also exert an adjustableforce opposing
bridge cycle is about 5 pN. Interestingly,these isometric
movement of the actin filament. When the tweezersapforce impulseslastedlonger when the ATP concentration
pliedonly a smallopposingforceand the experiment
was lower. This last findino is consistentwith the notion
was conducted in the presenceof adenosinetriphosphate that ATP binding to myosin must occur to allow detach(ATP),they observedthat the actin moved over the myo- ment of the cross-bridges(step 7 in the cycle in Fig.
sin bead in step-likedisplacements
of 11 nm. This obser- 9-7').
vation, made under "microscopicallyisotonic" conditions,

tends to pull this mobile point away from the 6xed one.
Here, stimulation causes shortening, provided that the
tension developed by the muscle is greater than the opp o > i n gl o a d . B e c a u steh e s es h o r t e n i n gos( ( u r < 1 (r o - 5 t d n l
load, they are relerred to as isotonic contractions (see
Fig. 9-128). Bolh isomeldc and isotonic contractionscan
be examined at different initial muscle lengths. Moreover,
they can be measured during individual muscle twitches
thar are evoked by single muscle action potentials, as well
as during other pattems of stimulatron.

Muscle Length InfluencesTension

Development By Determining the Degree of
Overlap Between Actin and Myosin Filaments
The isometricforce of contractions depends on the initial
length of the muscle flber. Unstimulated muscle may be
elongatedsomewhatby applying tension and stretchingit.
The tension measured before muscle contraction is referred to as passive tension (see Fig.9-12C). Because
muscle gets stiffer as it is distended, it takes increasing
amounrc of "passive"tension to progresslvelyelongatethe
muscle cell. lf at any fixed lengLh (i.e., isometric condilions) the muscle is stimulated to contract, an additional
active tension develops becauseof cross-bridgecycling.
The total measuredtension is thus the sum of the passive
and active tension. This incrementaLor dctiy tensionthe diflerence between total tension and passive ten
sion-is quite small when the muscle is less than app r o r i m a L e l7l 0 9 oo f r t s n o r m a lr e s t i n gl e n g t ht s e eF r g .o
12D). As muscle length increases toward its norrnal
length, active tension increases.Active terlsion is maximal
is near the normal
at a Length-fsually called l"-that
muscle length. Active tension decreaseswith further
lengthening, thus, active tension is again small when the
muscle is stretched beyond 150o/oof its normal resting
length. Although the relationship between muscle length
and tension has been best characterizedlor skeletal muscle, the tension of cardiac and smooth muscle also appears to depend on length in a similar manner.

This length-tension relationship is a direcr result of the

anatomy of the thick and ihin filaments within individual
sarcomeres(see Fig. 9-12D). As muscle length increases,
the ends of the actin filaments arising ftom neighboring Z
disks are pul1ed away from each other. When length is
increased beyond 150o/oof its resting sarcomere length,
the ends oI the actin filaments are nulled bevond the
end. ol rhe myosrr Flamenl. Urder this cond,tionn
.o
interaction occurc between actin and myosin filaments
and hence no development of active tension. As muscle
length shortens from this point, actin and myosin filaments begin to overlap and tension can develop; the
amount of tension developed corresponds to the degee
of overlap between the actin and the myosin hlaments.As
the muscle shortens further, opposing actin filaments
slide over one another and the ends of the myosin filaments and-with extreme degreesof shortening eventually butt up against the opposing Z disks. Under these
conditions, the spatial relationship between actin and myosin is distorted and active tension falls. The maximal
degree of overlap between actin and myosin fila
ments, and hence maximal active tension, correspondsto
a sarcomere length that is near its normal resting
Lengrn.

At Higher Loads,the Velocity of Shortening

ls Lower BecauseMore Cross-Bridges
Are
SimultaneouslyActive
Under isotonic conditions, the velocity of shortening decreasesas the applied load opposing contraction of the
muscie frber increases.This point is obvious; anyone can
lift a single French fry much faster than a sack of potaroes. As shown for any of the three blue curvesin Figure
9-l2E-each
of which represents a different initial
length of muscle-the relationship between velocity and
load is hlperbolic. Thus, the smaller the load applied to
the muscle, the greater its velocity of shortening. Conve$ely, the grcater the Load, the lower the veiocity o[
shorteninq.

9 / CellularPhysiology
of Skeletal,
Cardiac,and SmoothMuscle
A

EXPERII\,{ENTAL
PREPARAIION

Actinfilamenlwithpolystyrene
beadsaltachedat eachend

B ISOTONIC
30
20
Dispacement1o
{nm)
o

c tsot\,1ETRtc
10
8

')-

I":.* -"
I acrn moves (pN)
l
tn onecross- bridgecycle
0

0.0 0.5 1.0 1.5

Time(sec)

0.0

force oI
I a stnole
lcross-onoge
J cycre

0.2 0.4
Time(sec)

Microscopic measurementsof cross bridge force and dlsplacemenr.A, An aciin filanenr is anached at each end to a polysq.renebead.
FICURE 9-i3.
'opncal
iweezers, a 6nely focused beam of laser light, can '\rap rhe bead at lrs focal point and physically move rt. By adjuning the laser
The
intensity, the xpenmnter can alter the strength of th tlap (i e , rhe lorce wirh which the bead is heid). In this experimnr,rwo optical rweezerswere
used to suspend the actin filament above a coverglass Atlached !o lhis coverslip is a silica beed, and myosrn molecules are bound ro rhe bead. B, hr
an "isoionic experimnt, lhe lbrce between rhe actin filan1el1tand the fixed myosin/silica bead is kepr connan! by using a sLablelaser imensity. The
e lunction of time, the displacementof the polystyrene bead (bhc) ar?y from the cer,rer of rl,e Lrap. Thus. in one cross
experimnler
bridge cyc1e,lhe myosin acljn interaction pulls the polyslyrene bead approximately 11 nm aNay frolr the cenrer of lhe !rap. C, In an "isomerric
experimen!, the expeimenler measures,as a function o[ !ime. lhe extra force that needs to be apphed (i.e., inc]ease in laser inrensiry) ro keep lhe
polystyrene bead (blle) at a iixed position near lhe center of ihe trap. Thus. in one cross bddge c).cl, ihe myosjn aclin interaction exerrs a lorce of
approximately 5 pN. (Daia from Finer JT, Mehk AD, SpudrchJAr Characterizationof single actin-myosin inreraclions BiophysJ 68:291s 296s, 1995 )

The load (or tension) velocity relationship is perhaps

b , . t u n d e r > t o obdy . o - , d e r i n gt h e s i r u a L i odnt m / x i m u n
load for a resting muscle length (i.e., isonlelnccondirions).
This situation is representedby rhe upper blue cume in
Figure 9- 128. At any time, aLl the availablecross-bridges
are engagedin resisting the opposing force. None are left
over to make the muscle shorten. If the number of engaged cross-bridgeswere decreased,the muscle wouLd
lengthen. At a sLightly smaller load bur at rhe same isoo n i c m r . c l e l e n g t h .f e u e - , ' o s s b r i d g e .r e e o t o o e e n .
gaged to resist the opposing load. Thus, extra crossbridges are availableto ratchet the thick myosin filaments
over the thin actin nlaments, but at a very Low veLocity.
At a still lower load, even more cross-bddgesare available
for ratcheting the myosin over the actin, and the veLocity
increaseslurther. At very low Loads,it is reasonableto
expect that as lhe myosin filament slides along the actin
filament, only a tiny fuactionof the actin monomers need

to interact with myosin heads to overcome the Load.Un

der these conditions of vanishingly small loads, the speed
wiLh which rhe rhick and thin filamenrs sLideover each
other is limited only by the time that it takes for rhe
ATP-consumingcross-bridgecycle ro occur. With increasi n g , e l o , i t 1 r. h e o - o b a b i l i toyl a , r r n . n l o s i n L e r d r . i o n <
decreases.Thus, fewer cross-bridges are simultaneously
active al higher shortening velocitres, and less tension
develops.
Note that rhe upper blue cui'vein Figure 9 128 appLies
to a particular lnitlal length of the muscle, that is, the
restinglength. We already saw in Figure 9 12C that the
total isometric lension (i.e., the maximal load that the
muscle can sustain at zero veLociry)increaseswith initial
r u . c l e l e n g t \ . l h i s o - r n c . p . ei . c o n f i r m e dr r f i g u r e o l 2 t : t h e l o n g e r h e ' t r a e g L h .r ' r el a r g e r - " r a r m a l
load under zero veLocityconditions (i.e., the three different interceptswith the abscissa).In conrrast to this maxi

CellularPhysiology
of Skeletal,
Cardiac.and SmoothMuscle/ 9
SINGLEI\,4USCLE
TWITCHES B TEMPORAL
SUNII\,1ATION
C UNFUSED
IETANUS
(5 Hz)
(10 Hz)
(25Hz)

Stimulus
lrequency

FICURE9

I
Y

l+ t t

I
Y

14. Frequencysummarion of skeletalmuscLerwirches

rclo,irt.rpn<nn,rne

rpverl< rh

ihrc', <iino ra,-

tionship between muscle power and applied load. Muscle

does measurablemechanicaLwork only when it displaces
a load. This mechanicalwork (W) is the product of load
(F) and dispLacement(A{). Power (P) is Lherate at which
work is performed, or work per unit time (At):
Equation 9- I
P=w/At:FXAx/At
Becausevelocity (v) is Ar/At, it follows that
Equation 9- 2
P:FXv
For a given load (F), we can calculaLethe power by
reading the velocity (v) from the uppermost of the three
blue load-velocityrelationships1n Figure 9- 12E. Power is
maximal at intermediate loads (where both F and v are
moderate) and falls to zero at maximum load (where
r, : 9) and at zero Load(where F : 0)

At sufficier.rtlylow srimulalion fiequencies, the tension

deveLopedfaLls to the resling leve1 between individual
twitches (Fig. 9-14A). Single skeLetal-muscle
twitches last
)5

:rnd )Otl m.ec

dpnendino nn

rh"

,"^"

situation occurs, the second action potential stimulales a

twitch that is superimposedon the residual tension of the
first twitch, thereby achieving greater isometdc tension
t l - a nr h c 5 - s r ( c o m n a r eI o o 1 4 4 a n d B ) T h i s e l e c r r :
knowt] as summation.
lf multiple action potentials occur closely enough in
time, lhe multiple twitches car.isummate and thus greatly
increaselhe tension developed-Summation is more effective at increasing tension when the action potentials are
grouped more closely in time, as in Figure 9 14C. ln
other words, tension is higher when action potentials arc
evoked at hlgher frequency. Becausethis type of tension
enhancementdepends on lhe frequency of muscle stimulation, it is relerred to as frequency summation.
W l - e n t h e r l r m u l a r r o nf r c q u e n c l ' s i n , r e a s e d. u l r cientLy, the individual twitches occur so closely together
i n I T c t h a t t l e y l u s e ( s e eF i g o . * r ' a - d c a u ' e r h e
muscle tensior-rto remain at a sLeadypLateau.The state in
which the individual twitches are no longer disringuish,
able lrom each other is referred to as tetanus. Tetanus
ariseswher-rthe time between successiveaction potentials
is insulficient to retum enough Ca" back to the SR ro
Jower lCa''1, below a Level that iniriates relaxation. ln
lact, a sustained increasein [Ca'?*],persists untii the te,
tanic stimuius ceases.At stimulation frequencies above
the fusion frequency that causes tetanus, muscle frber
rph<r.n

ih.rei<p<

\,en'

lirrlp

In a Whole SkeletalMuscle,the Force

Developed May Be IncreasedBy Summing
the Contractionsof Multiple Fibers

In a SingleSkeletalMuscleFiber,the Force
Developed May Be IncreasedBy Summing
Multiple Twitches ln Time

lrpt*ern

D FUSED
TETANUS
(50Hz)

l+lt{'l{+t

mal /oad, which depends very much on length, maximal

velociiy is independent of length, as shown by the com
mon intercept of the family of curves with the ordinate.
The explanation lor this effect-as we have already
noLed-is thal maximal velocity (at no load) depends on
tl-re maximal rate of cross bridge turnover, not on the
iniLial overLapof the thin and thick filaments.
Thc

249

^f

r r u , c l e .A l t h o L , g eL a c hL w ' t . h i . c . r c . r e dh y a s - g l e m r . cle action potential, the duration of contracrion is Long

when compared with the duration of the exciting action
potential, which lasts only several milliseconds. Because
the muscle twitch far exceedsthe duration of the action
poLential,it is possible to inillate a second dctioil pofentidl
before a firsL contractionhas fully subsided. When this

In addition to determining the ftequency with which i[

stimulates a single muscLefiber, the central neryous system (CNS) can control muscle force by determining tl.re
number of indil'rduaL muscle flbers that it stimuLatesat a
given time. As each additional motor-neuron ce1I body
within the spinal cord is excited, those muscLehbers that
are part of the motor unif of that motor neuron are added
l o t h e L o n L r a ( l i npgo o l o l l i b c s f F i S o - l , l T h r se f l e c ir<
known as multiple-fiber sumrnation. Generally, smaller
motor neurons serye rrrotor units consisting of fewer individual muscle fibers. Becausea given excltatory stimulus
will generatea larger excitatory postslnaptic potential (p.

9 / CellularPhysiology
of Skeletal,
Cardiac,and SmoothMuscle

innervates one set of

muscle fibers.

A pool consistsof
many motor neutons,
eachof which
innervatesa motor
unit with the muscle.
F I C U R E9 1 5 . T h e m o L o ru n i t a n d t h e m o i o r , n e u r o np o o l

212) in motor neuronswith smallercell bodies,Lhesmall

motor units are recruited even with minimal neuronal
stimulation. As neuronal slimulatron intensi6es. larger
motor neurons innewattng larger motor units are also
r e . . . r p d l h e ) o u r p . .v p r p c t t r - r e n tO l l t r . r : n a I r n then larger and larger motor units is referred ro as the
size principle. The group of all motor neurons inneNaring a single muscle is called a motor-neuron pool.
Multiple-fiber summation, someLimes referred ro as
spatial sumrnation, is an important mechanism that allows the force developed by a whole muscle to be relatively constant in time. lt is true thar rhe CNS could
direct the lorce to be relatively constant over time merely
by driving a fixed number of moror units within the
muscle to tetanus, where the force fluctuations are very
small (see Fig. 9-14D). However, adding tetanic moror
unils would increase toial muscle force by rather large
individual incremen|s. lnstead, the CNS can activateindividual motor units aslnchronously so that some units are
developing tension while others are relaxing. Thus,
whole muscle lorce can be relativeLyconstant wirh time,
even when individual libers are not stimulared to tetanus.
Smooth, nontetanic contraction is essentialfor fine motor
control.

In CardiacMuscle,Increasing
the Entryof
the ContractileForce
Ca2*Enhances
Whereas frequencysummation and multiple-frber summation are important mechanismsfor regulating rhe strength
of skeletal-musclecontracLrons,these mechanismswould

not be consistentwith the physiological demands of car

diac muscle. Becausecardiac muscle must contract only
once wiLh each heartbeat and must fully relax between
each contractron, frequency summation is precluded. Fur,
I e - r ' ' r o | el .h ( r r e n : i r c e l e c lrl , , 1 \ o u ' l l n q h e l $ e e c - f diac myocytes, as welL as Lhe requirement rhar cardiac
muscle contracl hourogeneously,eliminates the potential
l o r r r r r i p l e[ ] 1 ,r. - u n r r d r i n n f h " r . i o r e t h e . r r e r g L ho l
cardiac muscle contracLionmust be regulatedby modulating the contracrile force generatedduring each indlvldual
muscle twiLch. This tlpe of reguLationis an impo ant
part of the adaptive responseto exerciseand is mediated
by norepinephrine, a neurotlansmilter released by the
sympathetrcnen ous system.
Becausean increasejn lCaz*], activatescontraction by
removing thc inhibitory influence o[ rhe regulatory proLeins.it is reasonableto consider that conLractilefunction
may be regulated eirher by modulatrng the magnitude o[
the rise in [Ca']*], or by altering rhe Car' sensirivity of
the reguiatory proteins. ln fact, both these urechanisms
are important in controlling the force of cardiac n.ruscle
contraction.
In cardiac muscle, a signilicanLproportion of rhe activator Ca2t enters the cell via vohage gated Car* channels
that open during the cardiac action potentlaL.Mosr of this
Ca']* infiux occurs via L-type Caz' channels. How does
norepinephrine increasethe contractile force of the hearr?
This hormone acts through rhe B+ipe aclrencrglcreceptor
Lo increasethe generation of cAMP, activate PKA (p. 97),
and rn turn phosphorylate the L rype Ca2* channels.
Lhereby increasing the passive influx of Carn. An increased lCaz*], leads to an increasein contractile force.
The cAMP pathway aLso appearc to lncrease Lhe Caz*
sensitivity oI the contractile apparatusby phosphorylaring
one or more of the regulatoryproteins Thus, cAMP causes
an increasein the lorce generaredfor any given lCar']1.
Reciprocalcontrol over Ca2t entry rs provided by cyclic
guanosrne monophosphare (cGMP) dependenLphosphor
ylation o[ the L-r)?e Cazt channels.AcetylchoLine,acLing
through muscarinic ACh receptors, raises inrraceLlular.
CGMP concentrations. In turn, the CGMPdependent
phospl.rorylaLion
of L-t1pe Ca:- channels. at sites distinct
from those phosphorylatedby the cAMP dependentkinase,
causesa decreasein Ca" influx during Lhe cardiac action
potential and thus a decreasein the lorce of contraction.
Ca']* entry may also be regulated indirectly by modulating other ion channels so that they eirher change rheir
Ca']* permeabiliry or alter rhe duraLion of the action pot e - t a N o r e p i n - p h - i n el.o r r r . a m p e T r ) i n , r p d > et t e
Ca']t permeability of voltage-gaLed
Na* channels.Receptor
transduction mechanisms that inhibit voltage-gared K'
curents may prolong the cardiac action potential and
thereby increase net Caz+ influx through L t),?e Cart
channels without modulatlng rhe Ca,' channels them
selves-

In Smooth Muscle,Contractile Force ls

EnhancedBy Increasingthe Entry of Ca2+,As
Well As By Increasingthe Ca2*Sensitivityof
the ContractileApparatus
Unlike skeletal muscle, in which force development re
sults from the summatron of inclividual muscle twitches,

CellularPhysiologyof skeletal,Cardiac,and Smooth Muscle / 9

indivldual smooth muscie cells can maintain a sustained

c o n L - a . l r o tnh a t , a n b e g r a d e di n . 1 q n g t \ q r e . r w r d e
range. Contractile lbrce in smooth muscie largely depends
on the relative balance between the phosphorylation and
dephosphorylation of MLCs. The rate of MLC phosphorylation is regulated by the Ca']+-CaMcomplex, whlcl.r in
turn depends on lertelsoJ tntracellular Ca1'. Smootl.r n.ruscle cells can regulate lCa'?*1,over a wider range rhan
' , . e l e t aal n d . a r d i r . m r r slre . a n l o r s e t e r a l, e a s o r - .F f s t ,
<olTr:moolh ru,cle ,.ellsdo not gereratedLiion polen
tials. Rarher, their membrane potential varies sLowly in
response to neurotransmlttersor hormones. This graded
response of V- allows flner regulation of Ca'?+influx
through voltage-gatedchannels. Second, release of Caz*
from intracellular stores may be modulated through neu
rotmnsmitter induced generation of intracellular second
messengerssuch as lP3-This modulation allows finer controL of Ca']* release than occurs in the SR Ca2* release
channel by L-t1pe Ca']* channels in skeietaLand cardiac
muscle.
A second level of control over contnctile force occurs
by reguLatlngthe Cr12+sensitivityof proteins that regulate
confraction. For example, inhibiting fiyosin lryht ch'tin
alters the balance berween phosphoryLation
phaspl:Lr'tast:
and dephosphoryLation,in effecl alLowing a greater coniraction at a lower [Ca']+],.Some neurotransmittersact by
inhibiting the phosphatase, whlch appears to occur
through activation of G-protein-coupled receptors. Ano t h e r n ' e c h a n i . m' o r g o v e m i n gL h e C a . e ' " r r n t y o f
proteins that regulate contraction is alteration of the Ca,t
sensirivity of the myosi[ light chain hinase.For example,
MLCK ltself is phosphorylaied at specilic sites by severaL
proteln kinases, including PKA, protein kinase C, and
Ca'z*-CaM dependent kinases.Phosphorylationby any of
these krnasesdecreasesthe sensitivity of MLCK to activa-

Smooth Muscle Maintains High Forceat Low

EnergyConsumption

257

Therefore,it is reasonableto expect that a decreasein the

detachment rate would allow a greater number of crossbridges to be maintained and would resuLtin a lower rate
ol crossbridge cycling and ATP hydroLysis.Thus, smoorh
muscle appears to be able to slow down cross-bridge
cyciing just belore detachment,a feat that can be accompLishedin skeletalmuscle (seeFig. 9-7) only at low ATP
levels (as in igor mortis).

DIVERSITYAMONG MUSCLES
Each muscle Lype (i.e., skeLetal,cardiac, and smooth) is
distinguishableon the basis of its unique histology, ECcoupling mechanisms,and regulation o[ contractiLefunc,
tion. However, even within each of the three categories,
muscle in different locations must serve markedly different purposes,with different demands for srrengrh,speed,
and fatigabiliry. This diversity is possible becauseof dif
lerencesin the expressionof specific isoforms for varlous
con[ractile and regulatory proteins (Table 9- L).

SkeletalMuscle ls Composed of Slow-Twitch

and Fast-TwitchFibers
Some skeletal musclesmusl be resistantto fatigue and be
able to maintain lension for relatively long periods, al,
though they need not contract rapidly. Examples are
muscles that maintain body posture, such as the soleus
-o*er
'n
nu>cleol tLe
part ol rhe leg.
c o n t r a s ts. o m e
muscles need to contract rapidly, yet infrequently. Examples are the exlraocular muscles, which must contracl
rapidly to redlrect the eye as an object oI vlsual interesl
moves about.
lndividual muscLe fibers are classified as siow twitch
(type I) or.lcst twltch (type II), depending on rheir rate of
fnn p

dp,eln.-""r

Thpcp

6her

rl-^

-'-iih

guished by their histologic appearanceand their ability to

resist fatigue.
Slow-twitch fibers (Tab1e9-2) are generally thinner
Smooth muscle is oiten called upon to maintain hlgh
and have a more dense capillary network surrounding
force for long periods. lf smooth muscle consumed ATP
them. Slow twitch fibers also appear red because of a
at rates similar to striaied muscLe,metabolic demands
large
amount of the oxygen-binding protein myoglobin
would be considerableand the muscle would be prone to
(p. 656) within the cytoplasm.This rich capil1arynetwork
fatigue. Unlike striated muscle, however, smoorh muscle
together with myoglobin lacilitates oxygen transpo to
is able to maintain high force at a low rate ol ATP
the slow-twitch fibers, which mostly rely on oxidative
hydrolysis. This low-energy consumptiontligh-tension
metabolism for energy. The metaboLicmachinery of the
state ls referred to as the latch state. The latch state in
slow-twitch fiber aLsofavors oxidaiiye metabolismbecause
5 r l o o r h m u n l e i - r n i q u e b e c a u . eh i g h r e n , o r c a n b e
it has low glycogen content and gLycolytic-enz1'rne
activity
maintained despite a decreasein the degree of muscle
b u . a - r . h m i t o . h o n d r i aal n d o r r d a t r r e - e n z y m
c oen l e n t .
activation by excitatory stimuli. As a result, force is mainFast-twitch fibers differ among themselves with re' a i n e da t l o w e rl e r c o f M l t K p h o s p h o ql a i o n .
spect to fatigability. Some fast-twitch fibers are fatigue
"
The mechanism underLying the latch state ls not enresistant; they rely on oxidative metabolism (type IIa)
Lirely known, although it appearsto be due in large part
and are quite similar to slow-twitch Iibers wirh respect to
[ o c L , n g e sr n t h e k . r e r i c ,o I a c r i n - n ' y o s icn o > s - b r i d g e myoglobin content (indeed, they are red) and metabolic
formation and detachment.Thesechangesmay be a direct
machinery. One important difference is that fast-twitch
result of a decreasein the rate at which dephosphorylared o v i d a t . v ef i b e r sc o n t a r na b . r d a n t g l v c o g e na n d h a v e a
c r o ) ) - b n d g e .d e t a c h .T e n , . o n i - d r r e r r l y r e l a L e qt o r i - e
greater number of mitochondria than slow-twitch fibers
number o[ attached cross-bridges.Furthermore, the prod o . l h e < e l e a r u r e se n ' u r e a d e q u r r eA T P g e n e r aot n t o
portion o[ myosin heads cross-bridgeclto actin is related
compensate for the increased rate of ATP hydrolysis in
to lhe ratio of attachment fates to detachment rates
fast-twitch fibers.

9 / Ce lulafPhysiology
of Skeletal,
Cardjac,and SmoothN4uscle

TABLE 9-I

Myosinheavychain

SKELETAL
SLOW0)
MHC.I

Myosinlight chain

SKELETALFAST SKELETALFAST
OXIDATIVE
FATICABLE
(ll.)
CARDIAC
0tb)

SMOOTH

MHC- b, ltx

MHC-c and -B

M H C - s M1 , 2
(multipleisoforms)

MLC-It -3f

MLC-It -3f

MLC-'lv, I a

MtC-17a,-17b

SERCA2a

5ERCA1

SERCAl

SERCA2a

SERCA2a,2b
(b>>>a)

Phospholamban

Present

Absent

Absent

Present

Present

Calsequestrin

"Fast"and "cardiac"

"Fast"

"Fast"

"Cardiac"

? "Cardiac"
? "Fast"

RyR'l

RyRl

RyR2

lP3R(3 isoforms)
RyR3

TroponinC,

Troponin C2

Troponin Cl

Calmodulin
(multipleisoforms)

MHC-lla

MLC.iaS,-1bS

sR Ca ATPase

Ca2*releasemechanisms RyRl (Ca,* release

channelor "ryanodine"recep-

toD
Ca2t sensor

TroponinCr

1,4,5"triphosphate
lPrR,
inositol
receptor;
SR,sarcoplasmic
reticulum.

O r h c r l a s tn r i L c h f i b e r . a r e n o r . a p a b l eo l s J l h c i e r l
oxidative metabolism to sustain contraction. Becausethese
flbers must rely on the energy that is stored within glycogen (and phosphocreatine),rhey are more easily fatigable.
Fatigable fast-twitch fibers (rype IIb) have fewer mitochondria and lower concentrationsof myogLobinand oxidative enryTnes.Becauseof their 1ow myoglobin content,
tlpe llb muscle fibers are white. They are, however, richer
r g l y c o l l t re
c r z l T l ed c l l \ l \ r h a no r h e rh b e rr l p e sa r e
I n r e a l i t v .s l o n - a r J f a s rr w r L c hh b e r . r e p r e s e nrrh e
extremes of a continuum of muscle fiber characteristics.
Moreover.eacl whole m-scle ': compoceool 5bei ol
each twLtch t1pe, although in any given muscle one of the
fiber qpes predominates. The differences between 6ber
t1.pes derive in large part from differences in isoform
expression of the various contractile and regulatory proteins (seeTable 9- 1).
Differencesin the rate of contraction, for example, may
be directly correlaled with the maximal rate of myosin
ATPase activity. As many as 10 different myosin heary

chain isoforms have been identified. lndividuaL isoform

expressionvaries among muscle q.pes and is developmentally regulated.At least four isoforms of the MHC protein
are expressedin skeLetalmuscle (MHC-I, MHClla, MHCilb, MHC-llx/d). For the most part, a muscle fiber type
expressesa single MHC isoform, the ATPase aciivity of
which appearsto correspond to the rate of contraction in
that fiber t'?e. Whereas most frbers expressone of these
isoforms, some fibers expressa combination of rwo different isoforms. These hybrid cells have rales of contraction
rhat are intemediate between the two pure fiber t1-pes.
Differencesin the rates and strength of contraction may
also resuh from differencesin myosin light chain isoform
expressionor from isoform differencesamong other com
ponents of the EC coupling process.Three skeLetaL
muscle isoforms have been identifred. MLC-las and MLC-]bs
are expressedin slow twitch flbers, whereas MLC,1f and
MLC-3f are expressedin fast-twitch fibers.
Isolorm differencesaLsoexist for the SR Ca2+ pump
(i.e., the SERCA),calsequestrin,the Ca2*-releasechannel,

TABLE9_2
SLOW TWIT(H

]A5T TWITCH

FAsTTWITCH

Synonym

Type I

Type lla

Type llb

Fatigue

Resistant

Resistant

Fatigable

Color

Red(myoglobin)

Red (myoglobin)

White (low myoglobin)

Metabolism

Oxidative

Oxidative

Clycolytic

Mitochondria

High

Higher

Fewer

Abundant

High

Clycogen

CellularPhysjology
of Skeletal,
Cardiac,and SmoothMuscle/ 9

d n d t r o p o r n ( . F u r t h e r m o r e' o m e p r o t e r n . .- r - r " La s
phospholamban, are expressedin one fiber type (sLow
twitch) and not the other.
One particuLarlyinleresting feature of muscle differenti. 'on rc rh/t lhe -t"..e de,ermtrations nol -tatLL.
T h r o u g he x e r r i , et r a i n i r So r c . l a n g e si n p a t t e r n so f n e u
ronal stimulation, alterationsin contractile and regulatory
p - o t e . n. s o l o r me x p r e so( n m . j y o c L u r l - o r c \ a - n p e . i L i s
possible for a greater proportion of fast-twitch fibers to
develop in a specific muscle with reperltive rraining. lt is
even possible to induce cardiac-specif,cisolorms in skeletal muscLe,grven appropriatestimulation pattems.

The Propertiesof CardiacCellsVarywith

Locationin the Heart
Just as skeletal muscle consistsof mukiple Fber types, so
too does heart muscle. The electrophystologicaland mechanicaLproperties of cardlac muscle vary with rheir location (i.e., atria versus conductrng systemversus ventricle).
Moreover, even among cells within one anatomic location,
functional differencesmay exist between muscle cells near
the surface of the heart (epicdrdlqlcells)and rhose lining
the intedor of the same chambers(endoccrdialcells).As in
skeletaLmuscle, many of these differencesreflecr differencesin isoform expressiono[ lhe various contraclile and
reguLatoryproteins. Although some of the protein iso
forms expressedin cardiac tissue are identical to those

expressedin skeletaLmuscle, many of the proteins have

c a r d r a c - : p e t i 1i ., o l o r m - l s e e T a b l p o - l l
lhe VHC in
heart, for example, exists in two isoforms, a and B,
which may be expressedalone or in combination.

Smooth Muscle Cells May Differ Markedly

Among Tissuesand May Adapt Their
Propertieswith Time Even in a Single Tissue
When one considers that smooth muscle has a broad
range of functions, including regulating the diameter of
blood vessels,propelling food through the gastrointesrinal
tract, regulating the diameter of airways, and delivering a
newborn infant from the uterus, ir is not surpising that
smooth muc.lc r. , odrticudrly diver>er;pe o, rr usc-le.n
addition to being dlstinguished as unitary or multiunit
muscle (p. 231), smooth muscle in different organs di
verges with respect to ner.,'eand hormonal conlrol, elec
L - i c ad c v l t y .a r d c h a r a c t e - r. , t o f L o n l r a c r i o n .
Even among smooth muscle cells within the same sort
of tlssue, important functional differencesmay exist. For
example, vascularsmooth muscle cells within rhe walls o[
two arlerioles lhal peduse different organs may vary in
their contractile response to various srimuli. Differences
may even exist between vascular smooth muscle cells at
two different points along one arterial pathway.
The phenotype of smooth muscle within a given organ
may changewith shifting demands.The uterus, for exam-

TABLE 9_3

SKELETAI.

CARDIAC

sMooTtl

Mechanismof excitation Neuromuscular

potentials
transmission
Pacemaker
Synaptictransmission
depolarization Hormone-activatedreceptors
Electrotonic
Fl6.+ri.:l
.^, 'nlih^
via gap junctions
potentials
Pacemaker
Electrical
activityof muscle cell

Actionpotentialspikes

Actionpotentialplateaus

Actionpotentialspikes,plateaus
Cradedmembranepotential
changes
Slow waves

Ca2*sensor

Troponin

Troponin

Calmodulin

Excitation-contraction
couplrng

L-typeCa,* channel(DHP
receptor)in T-tubule
membranecouplingto
Ca2*releasechannel(ryanodinereceptor)in 5R

Ca'z-entry via L-type Ca'*

channel(DHPreceptor)
triggersCa2*-induced
Ca2-release
from SR

Ca,* entryvia voltage-gated

Ca2*
cnannets
Ca2*-and lP3-mediated
Ca2*releasefrom 5R
Ca2*entrythrough storeoperatedCa2*channels

Terminatescontraction

Breakdownof ACh by acetylcholinesterase

Action potential repolariza- Myosinlight chain phosphatase

UOn

Twitch duration

20-200 msec

200-400 msec

Regulation
of force

Frequency
and multifiber
summation

Regulation
of calciumentry BalancebetweenMLCKphosphorylationand dephosphorylation
Latch state

Metabolism

Oxidative,glycolytic

Oxidative

200 msec-sustained

Oxidative

DHP,dihydropyridine;
ACh, acetylcholine;
lP3,inositol1,4,5-tdphosphate
receptor;MLCK,myosinlight chain kinase;SR,sarcoplasmic
reticulum.

9 / CellularPhysiology
of skeletal,Cardiac,and SmoothMuscle

d f - - r o o t hm u < c l e - t r e m ) o m e t n u - n p l e .i ' c o m p o < e o

that undergoes remarkable transformatlon during gestation as it prepares tor parturition (see Chapter 55). ln
addition to hypertrophy, greater coupling develops between smooth muscle cells through the increasedformation of gap junctions. The cells aLsoundergo changesin
their expression of contractile protein isoforms. Changes
in the expressionof ion channels and hormone receptors
f a c ir r a t er h y h m t r e l e c t r . c aalc t - v r L yT.h i s a c l y i t y l s c o o dinated across the myometrium by propagation of action
potentiaLsand increasesin lCa']*1,through the gap junc
tions. These rhythmic, coordinated contractions develop
spontaneously,but they are strongly influenced by rhe
hormone oxylocin, levels of which increasejust before
and during labor and just after pa udlion.
These differences in smooth muscle function amons
v a n o u >l : s 5 u e <
o r e v e - lo v e r r h p l i L e t L moel a ' i n s l e c e l
p r o b a b l y- e f e c t d i f l e r e n c ei,n p r o r e- r o r - r p o s t r i ; nI.n
deed, in comparison to striated muscle, smooth muscle
cells expressa wider variety of isoforms of contractile and
r e g u l a t o r vp r o L e i n 'r ' . e eT a b l e o l r . t h t s \ a r i e l y . s a
result of both multlple genes and altemarive splicing (p.
139). This richnessin diversity is likely to have imponant
consequencesfor smooth muscle cell function, although
the precise relationship between the structure and func
tion of theseprotein isoforms is not yer cLear.

Smooth Muscle Cells Expressa Wide Variety

of Neurotransmitterand Hormone Receptors
Perhaps one of the most impressive sources of diversity
among smooth muscle relates to differencesin response
to neurotransmitters,environmental factors, and circulating hormones. Smooth muscle cells differ widely with
rcspect to the t),?es of cell-surfacerecepiors that mediate
the effects of these various mediators. ln general,smooth
muscle celLseach expressa vadety of such receptors,and
receptor slimulalion may lead to eirher contractlon or
reLaxation.Many substancesact through different receptor
subqpes in ditferent cells, and these receptor subtlT)es
may acl through different mechanisms. For example,
whereas some neurotransmitter,4:rormone
receDtors mav
i odn c h a n n e l so.t h e r s/ c t t h r o u g hh e L e r o t r i
be .rgand-gare

meric G proteins that either act directly on targets or acr

through intraceliular second messengerssuch as cAMP,
cGMP, or IP, and DAG.
The list of neurotransmitterc,hormones, and environmentaLfactors regulating rhe function of vascular smooth
muscle cells alone is vast (see Chapter 22). A few of these
vasoacLivesubshnces include epinephrine, norepineph
rine, serotonin, angiotensin,vasopressin,neuropeptide Y,
nitric oxide, endothelin, and orygen. Identical slimuli,
however, may result in remarkabLydifferenr physiologic
responsesby smooth muscle in different locations. For
example,systemicafledal smooth muscle cel1srelax when
the oxySenconcentrationaround them decreases,whereas
pulmonary artedal smooth muscle contracts when local
orygen decreases(p. 699).
SeeTable 9-3 for a comparison of muscLeqpes.

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