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Cellular Physiology
of Skeletal, Cardi dc,
and Smooth Muscle
Michael Apkon
L-
ri"l'l
::;!1{gi;.t
,t|i..li'.,
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,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
Branchedstructureof cardiacmuscle
l\,4
icrofibril
Intercalateddisk
--:-*-;
i Desmosome
Z-line
FICURE9-1.
2r1
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.
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
Open Ca'--dependent
K" channels
Slow hlTerpolarization
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^
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.
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
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.
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
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
9 / CellularPhysiology
of Skeletal,
Cardiac,and SmoothMuscle
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
v ,r(
daarLi.
rr
--hridop-
in
m r r < ,l p
rhe
mtn.rn
r.rlp
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.
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.
CellularPhysiology
of Skeletal,
Cafdiac,and SmoothMuscle/ 9
241
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.
L-typeca2* \r
^h.nnal
ca2*
/nHo
T-fi'hr rla
receptor)
[inarraysof 4]
r
J ca2'
ca2* Mechanical
connectton
SRterminalcisterna
coupiing of excitation ro contraction in skeleLaland cardiac muscle. Smoothmuscle, in contrast, has more rudimentary and shaLlowinvaginationscalled caveoli (seeFig.
o_ B8).
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-
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).
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.
TERMINATINGCONTRACTION
lh,
rnp
Physiology
of Skeletal,
Cardiac,
andSmoothMuscle/ 9
Cellular
'r\ ( .,
Calreticulin
\
.=It
Ll"/
ll_.,::...
t't
1,:
|
(_t
',
Calsequestrin/
9 11. Mechanisms
ol Ca: removal liom Lhc cytqrhsm.
FICURE
r,pl-r-:,^r
Rr her
rrl.pn ip.rf.
i. h ofl.
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-
and
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.
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
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 )
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
rclo,irt.rpn<nn,rne
rpverl< rh
dpnendino nn
rh"
,"^"
ih.rei<p<
\,en'
lirrlp
In a SingleSkeletalMuscleFiber,the Force
Developed May Be IncreasedBy Summing
Multiple Twitches ln Time
lrpt*ern
D FUSED
TETANUS
(50Hz)
l+lt{'l{+t
249
^f
9 / CellularPhysiology
of Skeletal,
Cardiac,and SmoothMuscle
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
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
257
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).
dp,eln.-""r
Thpcp
6her
rl-^
-'-iih
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
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
TABLE9_2
SLOW TWIT(H
]A5T TWITCH
FAsTTWITCH
Synonym
Type I
Type lla
Type llb
Fatigue
Resistant
Resistant
Fatigable
Color
Red(myoglobin)
Red (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.
TABLE 9_3
SKELETAI.
CARDIAC
sMooTtl
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
Terminatescontraction
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
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