New Human Physiology Ch 2-Muscle and Cells Disorders
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Transcript of New Human Physiology Ch 2-Muscle and Cells Disorders
N e w H um a n P h y s i o l o g y | P a u l e v Z u b i e t a 2 n d E d i t i o n
C h a p t e r 2 : M u s c l e a n d C e l l s D i s o r d e r s
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C h a p t e r2
S t u d y O b j e c t i v e sTo define the concepts gap junc t ion, motor unit , s ynapt ic & neuromuscular trans fer , is ometr ic
and is otonic contrac t ion, plas t ic ity , pos t s ynaptic potent ials , and rec ruitment.
To desc r ibe the elec tromyogram, three types of motor units and three types of musc le t is sue
(s tr iated, smooth, and myocardial t is sue) , modulat ion of neurotransmiss ion with fac ilitat ion,
potent iat ion, neurotransmitters and receptors .
To explain the func t ion of the neuromuscular junc t ion, the s ynapses , the neurotransmitters , and
the control of the muscular force by frequency var iat ion and rec ruitment. To explain disorders of
the neuromuscular junc t ion, the s keletal musc les , the smooth musc les and the myocardium.
To use the above concepts in problem solv ing.
P r i n c i p l e sWaller ’s law of neuronal degenerat ion: When a motor axon has been severed, the rough
endoplasmic ret ic ulum accumulates proteins required for repair of the axon. The axon and the
myelin sheath dis tal to the injury die and are phagocy t iz ed. The neuroglial Schwann cells remain
aliv e, proliferate and form long rows along the pathway prev ious ly occupied by the dead axon.
The severed axon regenerate along this pathway .
Dale’s law: A s ingle neuron liberates only one neurotransmitter at all its s ynapses . Although the
law is frequently valid, there are several ex cept ions , where two or more co transmitters are
released at all the s ynapses of a s ingle neuron.
D e f i n i t i o n sExcitatory postsynapt ic potent ial (EPSP) refers to a trans ientdepolar iz at ion of a neuron
membrane. The combined effec t of EPSPs from hundreds of presynaptic terminals can summate
to evoke an ac t ion potent ial.
Gap junct ions are transmembrane protein pores between cells . The pores represent a low
elec tr ic al res is tance. Mos t elec tr ic al s ynapses c ontain many gap junc t ions allowing free passage
of ions and small molecules in both direc t ions when open.
Inh ib itory postsynapt ic potent ial ( IPSP) is a trans ient hyperpolar iz at ion of a neuron
membrane. The negativ ity of the res t ing membrane potent ial inc reases (normally 70 mV) and
summation of IPSPs may result in an effec t.
Isomet ric cont ract ion is a muscular contrac t ion at c ons tant length.
Isotonic cont ract ion is a musc le contrac t ion at c ons tant tens ion ( load) .
A miniature endplate potent ial is probably caused by the spontaneous release of a s ingle
acety lcholine ves ic le into the s ynaptic c left . This is called quantal release .
Motor un it r efers to one motor neuron and the group of musc le f ibres it innervates . All musc le
f ibres belonging to a cer tain motor unit are of the same type.
Neurot ransmission r efers to trans fer of s ignals from one neuron to another mediated
elec tr ic ally or chemically .
The neuromuscular endplate is the contac t zone between the axons of motor neurons and
s tr iated musc le f ibres . The acety lcholine containing ves ic les of the axon terminals dock on the
release s ites of the presynaptic membrane with high aff inity . The musc le cell membrane at the
endplate is folded in junc t ional c rypts . Nicot inic acety lcholine receptors are concentrated at the
openings of these c rypts .
Plast icity r efers to mechanical plas t ic ity of smooth musc le t is sue or to an amplif ic at ion produced
by s ynapses , which transmit better when frequently used.
Recru itment r efers to the inc rease in force and contrac t ion veloc ity of a musc le by ac t iv at ion of
more and more motor units .
Sarcomere is a contrac t ile unit of a musc le f ibr il c ontaining the halves of two Ibands with the A
band in between ( ie, the par t of the f ibr il between two neighbour Z lines ) .
Synapt ic t ransfer refers to the transmiss ion of s ignals from one neuron to another , and the s ite
of contac t between the two neurons is called the synapse .
E s s e n t i a l s
This paragraph deals with 1. Neuromuscular junct ions , 2. Synapses , 3. Skeletal muscles , 4. Smooth
muscles and 5. Cardiac muscle t issue .
1. Neuromuscular junct ions
The neuromuscular endplate is the contac t zone between the axons of motor neurons and s tr iated
musc le f ibres . Axon terminals have ves ic les containing acety lcholine (Fig . 2 1) . The ves ic les dock on
the ac t iv e zones or release s ites of the presynaptic membrane with high aff inity . The musc le cell
membrane at the endplate is folded in junc t ional folds or c rypts (F ig. 21) . Nicot inic acety lcholine
receptors (Chapter 6) are concentrated at the openings of these junc t ional c rypts . The release s ites
are located direc t ly over the acety lcholine receptors (F ig. 21) . The pos ts ynaptic membrane has
acety lcholines terase all over its sur face.
The nicot inic acety lcholine receptor is related to a ligand (acety lcholine) gated ion channel found not
only in the neuromuscular junc t ion, but also at all autonomic ganglia (Chapter 6) and in the central
nervous s ys tem (CNS) . The receptor is f ix ed into the pos t junc t ional membrane, whereas
acety lcholines terase is loosely attached to its sur face. The receptor has f iv e integral protein subunits
(2 , 1 , 1 , 1 ) , s ur rounding a central ion channel pore that is opened by the binding of 2
acety lcholine molecules to the 2 proteins (F ig. 21) . Opening of the ion channel inc reases the
conduc tance for small c at ions (Na+ and K+) ac ross the pos t junc t ional membrane, depolar is ing the
membrane potent ial of the cell. These ion channels are not voltagegated (not dependent on changes in
membrane potent ial) , lik e mos t cat ion channels in neurons , cardiac and s keletal musc le cell
membranes .
Fig . 21: The neuromuscular junct ion and in t racellu lar events. Acetylcholine = ACh. The ACh
receptor to the right is magnif ied .
The acety lcholineves ic les are probably already s tored c lose to the release zones , await ing the release
s ignal (F ig. 21) . When the ac t ion potent ial (AP) reaches the axon terminals , the axon membrane is
depolar is ed, and voltagegated Ca2+ channels are trans ient ly ac t iv ated. This causes Ca2+ to f low down
its concentrat ion gradient from the outs ide into the axon terminal. The inf lux of Ca2+ at the release
zones causes the ves ic les to fuse with the axon membrane, and empty acety lcholine into the 50 nm
wide c left by exocy tos is (F ig. 21) .
After c ross ing the s ynaptic c left by dif fus ion, acety lcholine binds to its receptor protein on the musc le
cell membrane. This binding complex opens the ion channel and inc reases the conduc tance for small
c at ions ac ross the musc le cell membrane. The inf luxes of Na+ depolar is e the endplate temporar ily , the
trans ient depolar iz at ion is termed the endplate potent ial (EPP) . The EPP dies away when acety lcholine
is hydroly sed to acetate and choline by the enzyme, acety lcholines terase . The EPP has a large safety
margin, as a s ingle ac t ion potent ial in the motor axon will produce an EPP that always reaches the
threshold potent ial in the musc le f ibre.
Rapid contrac t ion of the musc le f ibre is achieved by propagation of the musc le ac t ion potent ial along the
whole length of the musc le f ibre membrane and into the small, t r ansverse tubules , which penetrate all
the way through the musc le f ibre (T tubules in Fig . 21) .
The acety lcholine binding at the motor endplate inc reases endplate conduc tance and generates an
ac t ion potent ial (AP) in all direc t ions from the end plate (F ig. 21) . The elec tr ic al ex c itat ion of the
sarcolemma and the transverse tubules (T tubules ) dur ing the AP tr iggers – by an unknown mechanism
the sarcoplasmic ret ic ulum to release a pulse of Ca2+ (F ig. 21) . The Ca2+ channels opens trans ient ly
in the v ic inity of each sarcomere (F ig. 21) . The sarcoplasmic [Ca2+] inc reases from 10 7 to 10 6 M
(which is the threshold) . This Ca2+ dif fuses to the adjacent myofilaments , where they bind s trongly to
troponin C on the ac t iv e f ilament, and end the troponin tropomyos in blockade. This enables c yc lic
c rossbr idges to work as long as the high [Ca2+] is maintained, whereby contrac t ion occurs . A
cont inually ac t iv e Ca2+pump returns Ca2+ to the sarcoplasmic ret ic ulum, and another Ca2+pump in the
cell membrane also reduces sarcoplasmic Ca2+ . Then the thin f ilament is off duty , because Ca2+ is
withdrawn from its troponin C, the troponin tropomyos inblockade is rees tablis hed and relaxat ion
ensues . The terminal c is ternae of the sarcoplasmic ret ic ulum contain granules of c alseques tr in, a
protein that can bind Ca2+ and reduce the concentrat ion gradient (Fig . 21) .
Neurons with motor func t ion have the ability to s ynthes ise acety lcholine, because they contain choline
acety ltrans ferase . This enzyme cataly ses the produc t ion of acety lcholine from acety lCoA and choline.
Almos t all c ells produce acety lCoA and choline . Choline is also ac t iv ely taken up from the ex tracellular
f luid v ia a mechanism indirec t ly powered by the Na+K+pump. There is a 50% reuptake of choline from
the s ynaptic c left ; hence some choline mus t be s ynthes ized in the motor nerve.
The pos t junc t ional membrane depolar iz es spontaneous ly result ing in socalled miniature endplate
potent ials (MEPpotent ials ) . A miniature endplate potent ial is probably caused by the spontaneous
release of a s ingle ves ic le into the c left . This is called quantal release .
An endplate potent ial is prolonged when cholines terase inhibitors are present in the s ynaptic c left . This
is because these subs tances (eser ine, edrophonium, malathion, parathion etc .) inhibits the enzyme and
thereby protec ts acety lcholine from being hydroly sed by the enzyme. The life dangerous parathion
poisoning is desc r ibed in chapter 6. Under normal condit ions , the endplate potent ial is terminated by the
rapid hydroly s is of acety lcholine by acety l cholines terase.
Acety lcholine is a transmitter in the CNS, in all motor neurons , in all preganglionic neurons of the
autonomic nervous s ys tem and pos tganglionic parasympathet ic f ibres , and in a few pos tganglionic
s ympathet ic f ibres . The cholinergic receptor subtypes are shown in Table 62 .
2. SynapsesChemical s ynapses prevail in humans , but we also have elec tr ic al s ynapses in gap junc t ions .
A chemical s ynapse c ons is ts of a neuronal presynaptic terminal, a s ynaptic c left and a subsynaptic (or
pos ts ynaptic ) membrane with assoc iated receptor proteins (Fig . 22) . The chemical s ynapse is highly
developed in the CNS. I t c onduc ts the s ignal one way only , and has a charac ter is t ic synaptic delay .
The presynaptic axon terminal ty pically broadens to form a bouton terminaux (presynaptic terminal) .
Fig . 22. A synapse between a preganglion ic and a postganglion ic neuron.
1. The ac t ion potent ial, or iginat ing in the CNS, depolar is es the axon membrane by selec t iv e inf lux of
Na+ , which has a large elec trochemical gradient. Repolar iz at ion follows rapidly by selec t iv e K+
eff lux (F ig. 22) .
2. When the ac t ion potent ial reaches the presynaptic membrane, Ca2+ enters the terminal through
voltagegated Ca2+ channels .
3. Ves ic les containing transmitter , fuse with the presynaptic membrane and release their c ontents
of acety lcholine into the s ynaptic c left (Ca2+ induced exocy tos is ) .
4. T ransmitter molecules (acety lcholine, ACh) dif fuse ac ross the s ynaptic c left and bind to spec if ic
receptors , which are located into the pos ts ynaptic membrane (F ig. 22) . This ligand binding
elic its a trans ient opening of pores , which are spec if ic ally permeable to small c at ions . The
synaptic c left of a chemical s ynapse is about 30 nm.
5. The ACh receptor opens and allows inf lux of Na+, whereby the membrane depolar iz es and an
ac t ion potent ial is generated which propagates along the length of the pos tganglionic axon (Fig .
22) . This is an appropr iate response of the pos ts ynaptic cell to the received s ignal.
6. The effec t is rapidly terminated by the highly spec if ic enzyme acety lcholines terase, which
hydroly ses acety lcholine into two inac t iv e produc ts (acet ic ac id and choline) .
Inf lux of Na+ or eff lux of K+ through the pores of s uch receptors changes the pos ts ynaptic membrane
potent ial. I f the presynaptic ac t ion potent ial (AP) results in a pos ts ynaptic depolar iz at ion, the trans ient
is called an Exc itatory Pos tSynaptic Potent ial (EPSP) . I f the AP results in a pos ts ynaptic
hyperpolar iz at ion, the trans ient is called an Inhibitory Pos tSynaptic Potent ial ( IPSP) . Exc itatory
synapses often use glutamate as the transmitter . The pores are penetrated mainly by Na+, which enters
the cell, depolar iz es the membrane, and produces an EPSP.
The axon hilloc k on the cell body has a high dens ity of v oltagegated Na+ and K+ channels . The axon
hilloc k probably integrates the many s ynaptic potent ials , and from here the ac t ion potent ial is
generated. The dendr ites have voltagegated channels for K+ and for Ca2+. Recent ev idence sugges ts
that dendr ites also contain voltagegated Na+ channels , which are involved in elec trogenes is ( ie,
movement of c harge ac ross the membrane) .
Each neuron in the CNS is in contac t with up to 105 presynaptic axon terminals . Synaptic inputs are
integrated at the axon hilloc k by either spat ial or temporal summation.
Spatial s ummation oc curs when inputs from several axons ar r iv e s imultaneous ly at the same
pos ts ynaptic cell. Their pos ts ynaptic potent ials are addit iv e. EPSPs summate and move the membrane
potent ial c loser to the threshold level for f ir ing. Conversely , EPSPs and IPSPs cancel each other out.
Temporal s ummation oc curs when success ive APs in a presynaptic neuron follow in rapid success ion,
so that the pos ts ynaptic responses over lap and summate. Summation is poss ible because the s ynaptic
potent ial las ts longer than ac t ion potent ials by a fac tor of 10100 t imes .
Each indiv idual s ynapse contains receptors , ion channels , and other key molecules , which are sens it iv e
to the neurotransmitters released at the s ite. These spec if ic protein molecules are involved in s ynaptic
plas t ic ity and summation.
Elec tr ic al s ynapses . A gap junc t ion is a transmembrane pathway of low elec tr ic al res is tance that
connec ts the c y toplasm of adjacent cells . A gap junc t ion allows the membrane potent ial of the adjacent
cells to be elec tr ic ally coupled . Gap junc t ions form elec tr ic al s ynapses , which dif fer from chemical
s ynapses in that transmiss ion, is ins tantaneous .
An elec tr ic al s ynapse cons is ts of s everal protein pores , which c lose in response to inc reased
intracellular [Ca2+] or [H+] in a cell, thereby inc reas ing their res is tance. Open gap junc t ions exchange
ions and small molecules up to a molecular weight of 1000 Dalton.
Gap junc t ions are found in s imple ref lex pathways , where rapid trans fer of the elec tr ic al potent ial is
essent ial, and between nonneural c ells such as epithelial and myocardial c ells , smooth musc le cells
and hepatocy tes .
Neurotransmitters are div ided into c lass ical, rapidly ac t ing nonpept ides (Table 71) and putat iv e,
s lowly ac t ing neuropeptides (Table 72) all dealt with in Chapter 7.
Here is only desc r ibed the func t ion of GABA, neuropeptides and dopamine.
The major inhibitory t r ansmitters are GABA (gammaaminobuty r ic ac id) in the brain and gly c ine in the
spinal c ord. Binding of GABA to the GABA receptor opens the pore for Cl inf lux , whereby the
subsynaptic cell membrane hyperpolar is es (Fig . 23) . The inc rease in Cl c onduc tance s tabilis es the
membrane potent ial and dec reases the eff ic acy of exc itatory transmiss ion. The GABA receptor pore is
permeable to K+ bes ides Cl . The GABA receptor has a major inhibitory role in brain func t ion and is the
binding s ite for barbiturates (used as hypnotic s in anaes thes ia) and for benzodiazepines (used to
relieve anx iety ) .
Fig . 23 : A GABAA receptor in an inhibitory s ynapse.
The GABAA receptor shown here is related to sedation and mood , whereas the GABAB receptor
controls spas t ic ity (Chapter 7) . Pic rot in blocks the GABAchannel.
Glutamate, aspar tate and related ac idic amino ac ids are the mos t impor tant exc itatory transmitters in
the brain and spinal c ord. Exc itatory neurons possess exc itatory amino ac id (EAA) receptors . EAA
receptors are a family of receptors with at leas t four dif ferent ions channels : The Nmethy lDaspar tate
receptor (NMDA) , and three socalled nonNMDA receptors one of which is the glutamate receptor .
The NMDA receptor operates with K+eff lux , while Na+ and Ca2+ enters the subsynaptic neuron. Mg2+
and many ant iepilept ic drugs block the NMDA receptor channel (Chapter 7) . Opening of Na+ and Ca2+
channels , which allow an inc reased inf lux of Na+ and Ca2+, c ause the membrane potent ial to approach
the threshold level for exc itat ion. Both a reduced Cl inf lux to the neuron and a reduced K+eff lux move
the membrane potent ial towards the threshold level and poss ible exc itat ion. The NMDA receptor has a
separate gly c ine s ite.
Neuropeptides (Table 72) have s low exc itatory or inhibitory transmitter ac t ions . Pept ides cannot be
synthes ized locally in the axon terminals , because they do not have r ibosomes .
Fig . 24: Pept ide neurot ransmit ters
Peptides are water soluble, and ac t as hormones by binding to spec if ic cell s ur face receptors . Cell
sur face receptors are a family of guanos ine tr iphosphatebinding proteins , socalled GTPbinding or G
proteins , which control and amplify the s ynthes is of s econd messengers . Cell s ur face receptors for
neurohormones can func t ion as transpor t protein and possess enzyme ac t iv ity (F ig. 24) .
Neuropeptides are build by a sequence of amino ac ids . Neuropeptides are s ynthes ized in the cell
bodies of the neurons and transpor ted to the terminal buttons by rapid axonal transpor t (F ig. 24) . Some
neuropeptides are released together with a nonpept ide co transmitter (Table 72) .
Some neuropeptides are produced when a large mother pept ide is c leaved into several ac t iv e
neuropeptides . Neuropeptides are released from the nerve terminal near the sur face of its target cell,
and dif fuse to the receptors of the target cell. Low concentrat ions of neuropeptides typically affec t the
membrane potent ial by changing the conduc tance of the target cell to small ions . The ac t ion of
neuropeptides usually las ts longer than that of enzyme inac t iv ated transmitters . Following prolonged
synaptic transmiss ion, neuropeptides are deac t iv ated by proteoly s is .
Dopamine and other catecholamines der iv e from ty ros ine v ia DOPA, which s tands for the precursor 3,4
dihydroxy pheny lalanine. Dopamine is the ac t iv ely accumulated into s torage ves ic les in the nerve
endings together with noradrenaline and ATP. Dopamine ac t iv ates both presynaptic and subsynaptic D2
receptors (F ig. 25) .
Fig . 25: Dopamine receptors and the in teract ions w ith noradrenaline (NA) .
Noradrenaline can be ox idat iv ely deaminated by monoamine ox idase (MAO) located on the ex ternal
membrane of mitochondr ia (F ig. 25) . The enzyme COMT (catecholO methy l t rans ferase) can also
methy late noradrenaline to nor metanephr ine. MAO and COMT are impor tant in metabolis ing c ir culat ing
catecholamines . Reuptake of noradrenaline is the mos t impor tant terminator of its ac t ions .
Ac t iv at ion of both D2 receptors opens K+ channels and the inc reased outf lux of K+ hyperpolar iz es the
membrane. Blockage of the presynaptic D2 receptors in subs tant ia nigra with ant ips ychot ic drugs
reduces K+outf lux and inc reases dopamine produc t ion and release.
Loss of dopaminecontaining neurons in subs tant ia nigra results in the lac k of dopamine at the D2
receptors of the s tr iatal neurons . These neurons degenerate in Park inson's disease caus ing muscular
r igidity and hand tremor (Chapter 4) .
3. Skeletal musclesSkeletal or s tr iated musc les are attached to a s keleton. Str iated musc les are called s tr iated , because
they have a s tr ik ing banding pattern. Mic roscopy with polar is ed light reveals dark (opt ic ally anisotropic )
s tr iat ions or A bands alternat ing with light or opt ic ally is otropic s tr iat ions or I bands . Running along the
ax is of the musc le cell or musc le f ibre is the myofibr il bundles of f ilaments that are v is ible on elec tron
mic rographs . The A band contains the thic k f ilaments of myos in, and the I band contains thin f ilaments
of ac t in and tropomyos in (Fig . 26) . The thin f ilaments are anchored to a transverse s truc ture termed
the Z dis c (F ig. 26) . Each contrac t ile unit c ontains the halves of two Ibands with the Aband in
between. This unit is a sarcomere . Sarcomeres have a length of 2.32.5 m between the two Z dis c s at
res t. The central A band is a relat iv ely is otropic subs tance also termed the Hband with an M line of
dark ly s tained proteins that link the thic k f ilaments into a f ix ed pos it ion. Contrac t ion takes place by
s liding of the f ilaments .
The s liding of f ilaments agains t each other is called the s liding f ilament hypothes is , and s ince
contrac t ion works by c yc ling of millions of c rossbr idges , it is also called the theory of c rossbr idge
cyc ling .
The thin f ilaments are 11.2 m long and cons is t of small globular proteins that form two helic pear l
s tr ings . The double helix of ac t in is s uppor ted by a long, thin molecule of t r opomyos in that is s ituated
along the groove of the double s trands of ac t in (F ig 26) . Each tropomyos in molecule interac ts with 7
ac t in molecules on each s ide. Troponin is c omposed of 3 subunits : T roponinC binds Ca2+, t r oponinT
reac ts with tropomyos in, and troponin I inhibits the ac t inmyos in interac t ion, when Ca2+ is absent.
Dys trophin is another normally occur r ing c y toskeletal musc le protein.
The thic k f ilaments are 1.6 m long, and cons is t of large myos in molecules . Myos in is a dimer of almos t
500 kD. Each monomer cons is ts of one heavy chain and two light chains . The heavy chain cons is ts of a
helic al tail and a globular head (F ig. 26) . The light c hains are assoc iated with the head of the heavy
chain. Since myos in is a dimer , the doublehelix tail mus t end in two globular heads (F ig. 26) . The
globular heads contain the ATPase ac t iv ity and the ac t inbinding s ite. The light c hains control the rate
of c ross br idge c yc ling.
Fig . 26: Th ick and th in f i laments. The crossbridge cycle.
The c rossbr idge c yc le theory s tates that there are mult iple c y c les of myos inhead attachment and
detachment to ac t in dur ing a musc le contrac t ion. When myos in binds to ac t in, an ac t inomyos in complex
is formed with an ex tremely ac t iv e ATPase. The interac t ion between ac t in and myos in and the
hydroly s is of ATP is the bas ic process that conver ts chemical energy into mechanical energy .
Each c rossbr idge cons is ts of two heads . At res t the c rossbr idge from myos in is not attached to ac t in.
The globular myos in heads are or iented perpendicular to the f ilament ax is (F ig . 26) , and they have a
high s tandard aff inity for ac t in.
1. St imulat ion of a musc le liberates Ca2+ in the sarcoplasma, which removes the troponin
tropomyos in blockage of the ac t in, and ac t in can reac t with the binding s ites on the globular
heads . The c rossbr idge is now bound to the thin f ilaments (F ig. 26) .
2. The binding accelerates the release of ADP and P i f r om the ac t inmyos in complex , and the
attached global heads change conformation by 45o with respec t to the f ilament ax is . The head of
the c rossbr idge drags the thic k f ilament 10 nm along towards the Z dis c or at c ons tant length
a propor t ional force is developed. Mult iple repet it ions of this shor t s liding process is necessary
to result in an apprec iable musc le shor tening. In the absence of ATP, the c rossbr idge c yc le
s tops here and the binding is immobile ( r igor link and r igor mor t is ) .
3. The following s tage is the binding of ATP to the myos in heads , which weakens the binding to
ac t in and dis rupts the r igor link .
4. Then ATP is par t ially hydroly sed on the myos in head, and the result ing energy is s tored in the
perpendicular head, which has a renewed high s tandard aff inity for ac t in. I f Ca2+ is present, a
new c rossbr idge c yc le is init iated and may occur 100 t imes each s . With a c y c le movement of 10
nm this is 1000 nm per s for each half of the sarcomere.
Fig . 27: Force length d iagram
Force is required to s tretch a relaxed musc le, because musc le t is sue is elas t ic , and the force
inc reases with inc reas ing musc le length (F ig. 27) . The pass ive blue curve ref lec ts the proper t ies of the
elas t ic , c onnec t iv e t is sue, which becomes les s compliant or s t if fer with lengthening (F ig. 27) .
A musc le contrac t ion at c ons tant length is termed is ometr ic . Force is measured in Newton (N) , and one
N is the force required to accelerate a mass of one kg with an accelerat ion of one m s 2 . In musc les ,
the tradit ional express ion for force is s tress or tens ion in N per c ross sec t ional area of the musc le (N
m 2) , which is ac tually pressure (Pascal, Pa) . Here, the ordinate is force expressed as a percentage of
the max imal force (Fig . 27) .
1. The length at which max imum ac t iv e contrac t ile force is developed is called Lo , c or responding to a
sarcomere length of 2.15 m (F ig. 27) . Lo is the length of the musc le in the body when at res t. At this
length there is a max imum number of ac t iv e c rossbr idges (F ig. 27) . When an is olated musc le in an
is ometr ic force or s tress meter is s t imulated, the ac t iv e musc le force dec reases with the dec rease in
over lap between thin and thic k f ilaments ; at a sarcomere length of 3.65 m the is ometr ic force reaches
zero (F ig. 27) . The force is always propor t ional to the number of c y c ling c ross br idges interac t ing with
the thin f ilament.
2. Force also dec lines at musc le lengths les s than Lo (Fig . 27) . Thin f ilaments over lapping, and thic k
f ilaments colliding agains t Z dis c s cause this . The is ometr ic force ( s tress ) dec reases as the sarcomere
length is reduced, as shown with the sarcomere length of les s than 2.15 m (F ig. 27) .
3. When the ac t iv e musc le length is s tretched beyond any over lapping between the thin and the thic k
f ilaments the musc le can only develop a force of z ero ( see the sarcomere length of 3.65 m with an A
band of 1.6 m in F ig. 27) .
The lengths of the thic k and thin f ilaments of human s tr iated musc les are s imilar (1.6 and 1.2 m,
respec t iv ely ) . They generate max imal tens ion forces at Lo , c or responding to a sarcomere length of 2.2
m, namely 300 kN per m2 or kPa.
Musc le power or work rate (Eq. 21) is the produc t of musc le force (N) and shor tening veloc ity (m s 1) .
The max imal work rate of human musc les is reached at a contrac t ion veloc ity of 2.5 m s 1 . The max imal
work rate is thus (300 kPa *2.5 m s 1) = 750 kW per square meter of c ross sec t ional area.
Hill developed an equation for the shor tening veloc ity of is otonic musc le contrac t ions (Eq. 22) . The
equation is illus trated in Hills forceveloc ity diagram (Fig . 28) .
The max imum force is developed at the init ial length (F ig. 28 r ight: 18 g of load) . At 18 g there is no
shor tening – the length is unchanged. St imulat ion of the unloaded musc le results in max imum shor tening
veloc ity (100%) . An unloaded c rossbr idge can c yc le at max imal rate, indicated by max imal shor tening
veloc ity (F ig. 28 r ight) .
The shor tening veloc ity dec reases rapidly as the after load is inc reased desc r ibing a hyperbola (Fig . 2
8 righ t ) . With inc reas ing loads the latency is inc reased and the shor tening is reduced (4 and 9 g in Fig .
28 lef t ) . The latency depends on the length of thepreceding is ometr ic phase. The max imal veloc ity of
shor tening is direc t ly propor t ional to the myos in ATPase ac t iv ity . We inc rease the veloc ity of musc le
shor tening under a given load by the rec ruitment of addit ional motor units .
The long human arm musc les shor ten at a rate of 8 m per s . Musc les can bear a load of 1.6 t imes the
max imal force before the c rossbr idges are broken, but under such ex treme condit ions the work rate
(power ) of the musc le approach zero (no shor tening in F ig. 28 lef t) . This is also the case when a
person attempts to lif t a motor car the speed of shor tening is zero ( is ometr ic contrac t ion) . On the
other hand, the speed at which a pocket thief operates is probably impress ive, although the force is
minimal.
Max imal work rate occurs at a load of 1/3 of the max imal is ometr ic force of the musc le. Here the
contrac t ile s y s tem has opt imal eff ic iency in conver t ing chemical energy into mechanical energy .
Fig . 28: Hil l ' s forcevelocity d iagrams ( right ) and related shorten ing curves ( lef t ) .
A fur ther r is e in f ilament veloc ity seems to reduce the potent ial for ac t inmyos in interac t ion. The
c rossbr idge c yc ling rate falls as the load on the c rossbr idges inc reases (F ig. 28 r ight) .
In a musc le, the force of c ontrac t ion is graded by inc reas ing the frequency of ac t ion potent ials , and by
rec ruit ing more musc le cells . Prolonged c rossbr idge contrac t ion results in phys iological tetanus . This is
a prolonged musc le contrac t ion maintained by the prolonged Ca2+ inf lux caused by repet it iv e
s t imulat ion.
Human s keletal musc les cons is t of three func t ional ty pes of motor units . A motor unit is a motor neuron
with the musc le f ibres it innervates . All musc le f ibres belonging to a motor unit are of the same type.
The three types of musc le f ibres are charac ter is ed in Table 21 .
Table 21. St ructural, funct ional and h istochemical characterist ics o f tw itch f ibres.
Classif icat ion Red ( I) Red ( I IA) White ( I IB)
Slow ox idat iv e (SO) FOG FG
Intermediate Red White
Slow FR FF
Slow twitch Fas t twitc h red Fas t twitc h white
Myoglobin High High Low
Ox idat iv e enzymes High Intermediate Low
G lycoly t ic ac t iv ity Low Low High
G ly cogen Low High Intermediate
Mitochondr ia Intermediate High Low
Mitochond.ATPase Intermediate High Low
Sarcoplasmic ret ic . Intermediate Dense Dense
F ibre diameter Small Intermediate Large
Contrac t ions Pos tural Endurance Power ful
Shor tening veloc ity Low ( I) Intermed. ( I IA) High ( I IB)
Rec ruitment F ir s t Second Las t
Mos t human s keletal musc les are a mix ture of all three types of motor units , although the propor t ions
vary cons iderably .
Type I : The s low motor units contain s lowox idat iv e (SO) red s low twitch f ibres .They are adapted to
cont inuous pos tural musc le ac t iv ity . The f ibres have many mitochondr ia and a high content of myoglobin
( red f ibres ) . They depend on aerobic metabolism and the gly cogen content is high. Slow motor units
have weak but long las t ing contrac t ions ( s low reac t ion to a s ignal or twitc h) . The f ibres are small and
are f ir s t to be rec ruited. Dur ing light work these highly exc itable motor units ac t iv ate red f ibres suited
for prolonged ac t iv ity or endurance ac t iv it ies . Endurance training inc reases the ox idat iv e capac ity of
the ac t iv ated motor units , whereas s trength training inc reases cellular hyper trophy .
Type I IA: Fas t twitc h, fat igue res is tant (FR) motor units have type I IA twitc h f ibres with a high or
intermediate content of mitochondr ia, myoglobin, and gly cogen. These f ibres also rely upon ox idat iv e
metabolism ( fas t ox idat iv e gly coly t ic = FOG) and have a high level of both ox idat iv e and gly coly t ic
metabolism. The motor units prov ide contrac t ions of intermediate force and durat ion, and they res is t
fat igue. FOG f ibres are of intermediate s ize, and they are rec ruited before the white f ibres . This is in
accordance with the s ize rec ruitment pr inc iple : Small or intermediate motor units are eas ier to ac t iv ate
by exc itatory pos ts ynaptic potent ials (EPSPs ) than large neurons .
Type I IB: Fas t twitc h fat iguable (FF) motor units produce fas t c ontrac t ions ( fas t twitc h) , and fat igue
eas ily , as the name implies . Their large white f ibres , with their dense sarcoplasmic ret ic uli, are adapted
to ac t iv it ies requir ing large forces with rapid control of c ontrac t ion and relaxat ion. The fas t twitc h white
f ibres (also called type I IB due to the highes t shor tening veloc ity ) have few mitochondr ia, small amounts
of myoglobin (white f ibres ) , and depend on gly coly s is (high anaerobic metabolism) . They have only
small amounts of gly cogen ( fas t gly coly t ic = FG) . The FF motor neuron is large, the axon is thic k and it
branches so great ly that the FF motor unit innervates more musc le f ibres . This is why FF motor units
are capable of power ful c ontrac t ions . The cell body receives type Ia afferents . The FF units are
rec ruited las t and mainly dur ing max imal effor ts such as spr int ing. The produc t ion of ATP by gly coly s is
matches the high rate of ATP consumption.
We have three major metabolic sources of ATP:
1. Phosphoc reat ine, which is an immediate energy source used for intense white f ibre ac t iv ity such
as spr int ing. Lohmann's c reat ine k inase cataly ses the eff ic ient reforming of ATP from ADP by the
convers ion of a small phosphoc reat ine pool to c reat ine. Following exerc ise the oxygen debt is
repaid and the phosphoc reat ine pool is res tored (Chapter 18) .
2. The gly cogen s tores of the musc le produce ATP rapidly but ineff ic ient ly by gly coly s is , with
lac tate as the end produc t.
3. G lucose, free fatty ac ids , tr igly cer ides and amino ac ids in plasma are subs trates for ox idat iv e
phosphory lat ion. This is a mos t eff ic ient pathway and the s lowes t source of energy due to the
many s teps in the process (Chapter 20) .
4. Smooth musclesThe same molecules as in s tr iated musc le essent ially cause contrac t ion in smooth musc le, but the
intracellular organisat ion and the dynamic charac ter is t ic s are ent irely dif ferent (Table 22) .
Table 22: Characterist ics o f skeletal, card iac and smooth muscle cells.
Skeletal Card iac Smooth muscle
Diameter ( m) Up to 100 10 Up to 5
Length ( m) 200 000 50 Up to 200
T tubules Yes Yes No Simple caveoli
Regular sarcomers Dis t inc t Dis t inc t No Look smooth
Regular Z dis c s Yes Yes No but dense bodies
Regular myofibr ils Yes Yes Ir regular myofibr ils
T roponin Yes Yes No
Sarcoplasmicret ic ulum
Yes Yes Simple ret ic ulum
Gap junc t ions No Yes Yes (s ingleunit)
Ex tracellular Ca2+ No Yes Yes
Refrac tory per iod Shor t Long (300ms ) Long
Latency (ms ) 10 10 200
Twitch (ms ) 10100 300 3000
Res ting membrane pot.( mV)
80 90 50
Force High High Low maintained fordays
Energy cos t 300 fold High Low
Disorders Atrophy Cardiac As thma, hyper tens ion
Smooth musc les are called so because they lac k the dis t inc t sarcomer ic bands of s tr iated musc les .
Smooth musc le cells are spindleshaped and line the hollow organs and the vascular s y s tem; the
smooth musc le cells are ex tremely small (Table 22) . Smooth musc le cells contain a few thic k myos in
f ilaments , and many thin ac t in f ilaments attached to dense bodies by ac t in (helic al s arcomers ) . The
cells are without regular sarcomers , Z dis c 's , myofibr ils and T tubules . Smooth musc le cells lac k
troponin. Dense bodies are analogous to Z dis c 's , and some dense areas are attached to the cell
membrane. Smooth musc le cells do not contain a ty pical s arcoplasmic ret ic ulum, which can s tore and
release Ca2+. Ins tead some f ibres possess an analogous s imple ret ic ular s y s tem located near the
caveoli of the cell membrane. Caveoli are small invaginat ions of the membrane, s imilar to the T tubules
of s tr iated musc les . The more ex tens ive the ret ic ular s y s tem is in the smooth musc le f ibre, the higher is
its shor tening veloc ity due to release of Ca2+ mediated by IP3 . Smooth musc le cells maintain large
forces almos t cont inually at ex tremely low energy cos ts .
The same tens ion or tone is maintained for days in smooth musc le organs ( intes t ine, ur inary bladder ,
gall bladder ) and can be obtained in s tr iated musc le at high energy cos t (up to 300 t imes the smooth
musc le rate of ATP consumption) .
Smooth musc le cells are ex tremely sens it iv e to ex tracellular [Ca2+] .
Dur ing an ac t ion potent ial the inward f lux of ions is not Na+, but Ca2+ through s low Ca2+ channels . They
open mainly in response to a ligand binding, but we have also voltagedependent Ca2+ channels .
The force length relat ion is qualitat iv e s imilar to that of s tr iated musc les , so the s liding f ilament
mechanism is probably analogous (Fig . 26) .
The smooth musc le mechanism is spec ial, because s t imulat ion results in a maintained is ometr ic force
with s trongly reduced veloc it ies . Smooth musc le contrac t ions are ex tremely s low. Ca2+ probably
regulates the number of ac t iv e c rossbr idges in smooth musc le s lowly and indirec t ly .
Smooth musc le cells contain some mitochondr ia, and they show a s low contrac t ion pattern
super imposed on the las t ing tonus . Smooth musc le contrac t ions typically las t for 3 s , in contras t to
s tr iated musc le with total c ontrac t ion per iods of 10100 ms . Since the energy demand in smooth musc le
is ex tremely low, it is balanced by the ox idat iv e ATP synthes is . Smooth musc le cells do not have an
oxygen debt as s tr iated musc les do, although they produce large amounts of lac tate . This is probably
because the ATPsynthes is ing gly coly t ic mechanism is located in the cell membrane and is linked to the
ATPut ilis ing Na+K+pump. Smooth musc le contains far fewer myos in f ilaments than s tr iated musc le.
The myos in c rossbr idge heads of smooth musc le contain an is oenzyme with much les s ATPase ac t iv ity
than that of s tr iated musc le. Ca2+entr y through the cell membrane is much s lower than internal release
of Ca2+.
A contrac t ing smooth musc le f ibre releases Ca2+ f r om two pools . The large ex tracellular f luid pool is
essent ial. In the f ibre that possesses a sarcoplasmic ret ic ulum s imilar to the sarcoplasmic ret ic ulum of
s tr iated musc le, there is a fas t intracellular pool. The smooth musc le cell membrane contains a
3Na+2K+pump, a delayed K+ channel, a ligandac t iv ated and a voltagedependent Ca2+ channel, a
sarcolemmal Ca2+pump, and a Na+ Ca2+exchanger (Fig . 29) .
1. A s t imulatory ligand is bound to membrane receptors for G proteins and for ligandgated Ca2+
channels (F ig. 29) . The major Ca2+ inf lux takes place through the ligandgated (noradrenaline)
and the voltagegated Ca2+ channels . The Ca2+ inf lux depolar iz es their membrane, whereby
Ca2+ fur ther permeates the membranes . The depolar iz at ion by ligand binding thus indirec t ly
opens the voltagegated channels .
2. When a s t imulus ac ts on ret ic ular receptors v ia a G protein it ac t iv ates phospholipase C.
Phospholipase C hydroly ses phosphatidy l inos itol diphosphate (PIP2) into IP3 and diacy lgly cerol,
DAG (F ig. 29) .
Fig . 29: Cont ract ion and relaxat ion in smooth muscle cells. The l igand is acetylcholine in
visceral cells and noradrenaline, ATP and pept ide hormones in vascular smooth muscle cells.
3. IP3 is bound to a receptor on the s imple sarcoplasmic ret ic ulum and this second messenger
binding elic its a controlled release of Ca2+ f r om the ret ic ulum. Hereby , the sarcoplasmic [Ca2+]
r apidly inc reases above the threshold for contrac t ion (0.1 M) .
4. The c rossbr idge c yc ling is regulated by a myos in light chain k inase (MLC k inase) dependent
upon both Ca2+ and calmodulin. The phosphory lat ion of myos in to myos inphosphate is
dras t ic ally accentuated by the binding of 4 Ca2+ calmodulin to MLC k inase forming a complex .
The phosphory lated light chain myos in reac ts with ac t in in the thin f ilaments and contrac ts . The
rate of s liding and of ATPsplit t ing is up to 1000 fold s lower than in s tr iated musc les .
5. Ca2+ is ac t iv ely pumped out of the cell by an ATPdemanding Ca2+pump and through a Na+
Ca2+exchanger (ant ipor t) . The ant ipor t uses the energy of the Na+gradient for inf lux . Reuptake
into the poor ly developed sarcoplasmic ret ic ulum and the mitochondr ia is s low compared to
cardiac and s keletal musc le t is sue.
6. Below the Ca2+ threshold the myos in light chains are dephosphory lated by myos in light chain
phosphatase and the contrac t ile s truc tures relax .
7. The Na+K+gradient ac ross the cell membrane is maintained by the Na+K+pump (Fig . 29) .
When the high intracellular [Ca2+] dur ing an ac t ion potent ial is lowered again towards the res t ing level,
the cell r elaxes . This is accomplis hed by s t imulat ion of the sarcolemmal Ca2+pump, and by blockade of
both Ca2+ input and Ca2+ release.
Metar ter ioles and precapillary sphinc ters without nerve f ibres can s t ill r espond to the needs of the
t is sue by the ac t ion of local t is sue vasodilatators . The following fac tors cause smooth musc le
relaxat ion, and therefore vasodilatat ion: Adenos ine, NO , lac k of oxygen, excess CO 2 , inc reased [H+] ,
inc reased [K+] , diminished [Ca2+] , and inc reased [ lac tate].
Endothelialder iv ed relax ing fac tor (EDRF) is recent ly shown to be nitr ic ox ide (NO) . Ac t iv at ion of
endothelial c ells produces NO from arginine, and NO dif fuses into the smooth musc le cells . NO
s timulates direc t ly the enzyme guany latec yc lase , and by that intracellular [cGMP] elevates .
Cir culat ing acety lcholine contrac ts the ar ter ial smooth musc les when bound to cholinergic receptors .
Smooth musc le cells grow (hyper trophies ) as a response to the needs of the body , and they also retain
the capac ity to div ide.
Dur ing hyper tens ion the lamina media of the ar ter ioles hyper trophies which inc reases the total
per ipheral v ascular res is tance in the s ys temic c ir culat ion. These topic s are fur ther developed in
Chapter 9 .
Dur ing pregnancy the ( s ingleunit , s ee below) smooth musc les of the myometr ium are quiescent and
contain few gap junc t ions under the inf luence of proges terone. At term the myometr ium grows and the
number of gap junc t ions inc reases , due to the high oes trogen concentrat ion. Now the myometr ium is
well prepared for the coordinated contrac t ions dur ing par tur it ion ( s ee Chapter 29) .
Smooth musc le changes length without marked changes in tens ion. Init ially , there is a high tens ion
developed upon s tretching; then the tens ion falls as the myos in and ac t in f ilaments are reorganised by
s lowly s liding agains t each other . A sudden expans ion of the venous s ys tem with blood results in a
sharp r is e in pressure followed by a fall in pressure over minutes . The smooth musc le f ibres in the
walls of the venous s ys tem are highly compliant, because they have accepted a large blood volume
without much r is e in pressure (delayed compliance) .
Smooth musc le cells are frequently involved targets in diseases such as hyper tens ion, s troke,as thma,and many gas trointes t inal diseases .Smooth musc le cells can be div ided into mult i unit smooth musc leand s ingleunit smooth musc le.
Fig . 210: Cont ract ion of mult iun it smooth muscle cells (vascular) . A sing le cont ract ion is
elicited by an elect rical st imulus and later acetylcholine elicits tetanus. Cont ract ion of mult i
un it smooth muscle is cont ro lled by ext rinsic innervat ion or by hormones. Mechanical contact
junct ions between the cells are not found.
1. In mult i unit smooth musc le t is sues each cell operates ent irely independent of other cells and the
cell does not communicate with other musc le cells through gap junc t ions . The dis c rete cells are
separated by a thin basement membrane and often innervated by a s ingle neuron, and their main
control is through nerve s ignals . Thousands of smooth musc le cells belonging to the mult i unit
ty pe join by the common innervat ion in a func t ional s yncy t ium . Mult i unit smooth musc le is found
in the eye ( the c iliar y musc le and sphinc ters as the ir is musc le of the eye) , in large ar ter ies , in
the vas deferens , and in the piloerec tor musc les that cause erec t ion of the hair s . These musc le
cells are normally quiescent, insens it iv e to s tretch and they are ac t iv ated only through their
autonomic nerves . Each musc le is composed of mult iple motor units , hence the name: mult i unit
smooth musc les . The nerve f ibre branches on a bundle of smooth musc le f ibres , and form
junc t ions with var ic os it ies f illed with transmitters . These junc t ions are analogous to the
neuromuscular junc t ions of s tr iated musc les . The neurotransmitters are acety lcholine and
noradrenaline. Mult i unit smooth musc les have developed a contac t junc t ion with shor ter latency
than the s lowly operat ing dif fuse junc t ions mainly found in the s ingleunit ty pe.
2. Singleunit smooth musc le cells are ar ranged in bundles such as the ar rangement in a v is cera
eg. intes t ine, uterus and ureter (Fig . 211) . These smooth musc le cells commun icate through
hundreds of gap junc t ions , s eparat ing the cell membranes by only 23 nm, and from pacemaker
t is sue of var iable locat ion, ac t ion potent ials are generated init iat ing a contrac t ion of the musc le.
In this respec t s ingleunit c ells resemble the cardiac musc le.
Fig . 211: Sing leunit smooth muscle cells resemble card iac muscle. Act ivity propagates f rom
cell to cell through gap junct ions forming an elect rical syncyt ium. The dense bodies and dense
areas contain alphaact in .
Ac tion potent ials generated in one cell c an ac t iv ate adjacent cells by ionic cur rents spreading rapidly
over the whole organ and secur ing a coordinated contrac t ion as though the t is sue were a s ingle unit or
a syncy t ium . These cells are charac ter iz ed by their s pontaneous motility and by their s ens it iv ity to
s tretch. The spontaneous ac t iv ity is usually modif ied by the autonomic nervous s ys tem. Visceral
smooth musc le undergoing per is tals is , generates propagating ac t ion potent ials from cell to cell.
O ther cell tocell c ontac ts are desmosome's and intermediary junc t ions subserv ing s truc tural c ontac t.
These intermediary junc t ions trans fer mechanical force from one smooth musc le cell to another on the
plasma membrane, caus ing the s ingleunit smooth musc le cell to func t ion lik e a s tretch transducer .
5. Cardiac muscle tissue
Myocardial c ells are built of regular sarcomers jus t lik e the s keletal musc les , and they are contrac t ing
fas t. Myocardial c ells form an elec tr ic al s yncy t ium in the same way as the s ingleunit smooth musc le
cells . The charac ter is t ic s of myocardial, s keletal and smooth musc le cells are presented in Table 22 .
Myocardial c ells are mononuc lear and the myoglobin, enzymatic and mitochondr ial c ontent are large jus t
as the red f ibres of s keletal musc les . The metabolism of myocardial c ells is s imilar to that of red
skeletal f ibres , both being des igned for endurance rather than speed and s trength. The oxygen supply
to the hear t musc le mus t be maintained, if it is to s ynthes ise ATP at a suff ic ient rate. Myocardial c ells
depr ived of oxygen for 30s cease to contrac t.
Myocardial c ells mos t resembles smooth musc le in its auto rhy thmic ity and s yncy t ial func t ion.
Pacemaker cells in the s inus node determine the normal cardiac frequency , because they send out
spontaneous ac t ion potent ials along the conduc t ion s ys tem of the hear t with a higher frequency than
any other cells in the hear t. Vagal s t imulat ion releases acety lcholine at the pacemaker cells .
Acety lcholine inc reases the K+permeability , whereby K+ leaves the cell and hyperpolar iz es the cell
membrane. This is why the pacemaker ( cardiac ) frequency is reduced by vagal nerve s t imulat ion.
Sympathet ic s t imulat ion or adrenaline reduces the K+permeability , s o the depolar iz at ion is shor tened,
and the pacemaker frequency inc reased.
The prolonged ac t ion potent ial c harac ter is t ic for myocardial c ells is init iated by an abrupt Na+ inf lux
(phase 0) through fas t Na+ channels jus t as in the s tr iated musc les . The AP plateau is due to a s low
Na+Ca2+ channel, which deliv er Ca2+ for the contrac t ion ac t iv at ion. The ac t ion potent ial releases Ca2+
f r om the sarcoplasmic ret ic ulum to the sarcoplasma. The effec t is dis tr ibuted by the cardiac T tubule
sys tem.
Cardiac contrac t ion by c rossbr idge c yc ling depends on the presence of ex tracellular Ca2+ jus t as in
smooth musc le t is sue. Therefore, use of Ca2+antagonis ts reduces the contrac t ile force of the hear t,
whereas drugs , which inc rease Ca2+permeability ac ross the membrane, improve the contrac t ion. In the
hear t, Ca2+ inf lux tends to prolong the depolar iz at ion jus t as in smooth musc le cells . The cardiac
gly cos ide, digox in, s elec t iv ely binds to and inhibits the sarcolemmal 3Na+2K+pump, which leads to an
inc rease in intracellular Na+ . Although the Na+eff lux is inhibited, the redundancy of Na+ af fec ts the
Na+Ca2+exchanger (3 Na+ out for one Ca2+ into the cell) , leading to an inc rease in cellular Ca2+ and
in the force of c ontrac t ion. This is the mechanism of the inc rease in contrac t ile force by digitalis
gly cos ides .
P a t h o p h y s i o l o g yThis paragraph deals with 1. Disorders o f the neuromuscular junc t ions (myas thenia grav is ) , 2.
Skeletal muscle d isorders ( dy s trophia, dys tonia, musc le injur ies ) , 3. Smooth muscle d isorders
(as thma, hyper tens ion etc ) and 4. Myocard ial d isorders ( c oronary ar tery disease, ar rhy thmias , and
chronic hear t disease) .
1. Disorder of the neuromuscular junction (Myasthenia gravis)
This ser ious disease is acquired, but the cause is unknown. The development of this autoimmune
disorder may be related to other diseases . Rheumatoid ar thr it is treated with Dpenic illamine has
resulted in myas thenia grav is . More than 50% of the myas thenia pat ients have thymic hyperplas ia and
some pat ients have a real thymoma .
Many of these pat ients have an inc reased blood concentrat ion of ant ibodies agains t their own
acety lcholine receptor protein . There is a dec reased dens ity of receptor proteins on the pos t junc t ional
membrane. This was shown by the use of radioliganded tox ins from poisonous snakes (which bind
ir revers ibly to the acety lcholine receptor protein) .
The pat ients are t ir ed and the musc les are ex tremely weak . This is par t ic ular ly so for the prox imal limb
musc les , the ex traocular musc les and the neck musc les , whereby the pat ient has dif f ic ult ies in lif t ing
the head. Mas t ic at ion and swallowing is a dif f ic ult process .
Fig . 212: Neuromuscular junct ion w ith ant ibodies and decreased density o f acetylcholine
receptors in a pat ient w ith myasthenia gravis.
As jus t mentioned the blood of mos t pat ients with myas thenia grav is contains autoant ibodies agains t
acety lcholine (ACh) receptor proteins on the cell s ur faces of the motor end plates etc . The autoant ibody
competes for the ACh receptor and inhibits s ynaptic transmiss ion, so muscular contrac t ion is great ly
inhibited. Depos it ion of immune complexes eventually des troys the ACh receptor protein.
Intravenous injec t ion of an antic holines terase improves the musc le s trength immediately , but the
benefic ial ef fec t is gone within 3 min.
Thymec tomy improves the condit ion and the prognos is also in the group of pat ients without thymoma.
Oral ant ic holines terase ( s uch as py r idos t igmine) has benefic ial ef fec t over 24 hours . They inhibit the
enzyme acety lcholinees terase, and thereby prolong the effec t of naturally occur r ing acety lcholine on
the receptors . In severe cases this treatment is ineff ic ient, and immunesuppressants such as
cor t ic os teroids are sometimes favourable.
2. Skeletal muscle disorders
Muscular dys trophy is an inher ited disorder of s keletal musc les . Duchenne muscular dys trophy is an X
linked recess ive musc le disorder charac ter iz ed by the absence of dys trophin in the s tr iated musc les
and in the myocardium. The locus is localis ed to the Xp21 region of the X chromosome. Dys trophin is a
normally occur r ing c y toskeletal musc le protein. The pat ient is a boy , who has to c limb up his legs in
order to reach the erec t pos ture. Typically , there is prox imal weakness with compensatory
pseudohyper trophy of the calves . There is no cure and the pat ient dies from myocardial damage.
Dys tonias are prolonged musc le contrac t ions leading to muscular spasms . There is a s imultaneous
ac t ion of oppos ing agonis t and antagonis t groups that produce abnormal pos tures . Dys tonia is painful
and par t ic ular ly res is tant to treatment.
Dys tonia musculorum deformans begins in childhood with generaliz ed spasms that affec t gait and
pos ture. In mos t cases the cause is a genetic defec t.
Spasmodic tor t ic ollis c auses the head to turn ( tor t ic ollis ) or change pos ture. Pat ients with a tr igger
zone on the jaw benefit f r om acupressure here.
Musc le injur ies are dealt with in Chapter 18 .
3. Smooth muscle disorders
The mos t impor tant disorders are as thma (Chapter 14) and sys temic hyper tens ion (Chapter 12) .
Smooth musc les are also involved in a disorder of swallowing (achalas ia) , where the myenter ic plexus
and the lower oesophageal sphinc ter fail to respond with recept iv e relaxat ion, and the food accumulates
in the oesophagus . O ther disorders of the gas tro intes t inal smooth musc les are also treated there.
4. Disorders of the myocardium
Coronary ar tery disorders ( smooth musc les and myocardial disease) and conges t iv e hear t disease are
treated in Chapter 10 , and cardiac ar rhy thmias in Chapter 11 .
Only direc t therapeutic uses of the s ys tems developed t ill now are desc r ibed here.
Nitrogly cer ine, nitropruss ide and s imilar drugs relax smooth musc les by trans fer of NO from
endothelial c ells . NO inc reases intracellular [cGMP] (Fig .111) , which is the bas is for the benefic ial
effec t of the drugs on cardiac c ramps . These second messengers ac t iv ate protein k inases that
phosphory late effec tor proteins such as Ca2+pumps and K+ channels . Such vasodilatators s t imulate
the sarcoplasmic Ca2+pump , inhibit Ca2+ inf lux and s t imulate K+eff lux through the delayed K+ channel
( reduces the exc itability ) . Hereby , the high intracellular [Ca2+] dur ing an ac t ion potent ial is lowered
towards the res t ing level (10 7 mM) , and the smooth musc le cell r elaxes produc ing vasodilatat ion.
Equat ions
Muscle power (or work rate) equals the produc t of musc le force and shor tening veloc ity
Eq. 21 : Power (W) = Force (N) * Veloc ity (m s 1) .
Hill ’s equat ion . The forceveloc ity curve is shown in Fig . 27 . The curve f its Hill’s equat ion:
Eq. 22 : Init ial s hor tening veloc ity ( v ) = (Po P) *b/(P + a)
where P is the force or load ac t ing on the musc le, Po is the max imal is ometr ic force or load, a is a
cons tant with the dimens ions of a force, and b is a cons tant with the dimens ions of v eloc ity .
S e l f a s s e s s m e n t
Mult ip le Choice Quest ions
I . Each of the fo llow ing f ive statements have False/True opt ions:
A. Motor neurons s ynthes ise acety lcholine unrelated to their c ontent of c holine
acety ltrans ferase.
B. There is a high dens ity on the subsynaptic membrane of spec if ic acety lcholine receptors .
C. The receptor protein for acety lcholine contains a voltagegated channel for cat ions .
D. Binding of acety lcholine elic its a trans ient opening of ionophores , which are spec if ic ally
permeable to small ions .
E. Park inson's disease is poss ibly caused by los s of dopamine containing neurons in the
subs tant ia nigra.
I I . Each of the fo llow ing f ive statements have False/True opt ions:
A. Nitrogly cer ine, nitropruss ide and s imilar drugs contrac t smooth musc les by trans fer of nitr ic
ox ide from endothelial c ells .
B. All myas thenia pat ients have a thymoma.
C. Dur ing hyper tens ion the lamina media of the ar ter ioles hyper trophies which inc reases the total
per ipheral v ascular res is tance in the s ys temic c ir culat ion.
D. The nicot inic acety lcholine receptor is related to an acety lcholinegated ion channel found not
only in the neuromuscular junc t ion, but also at all autonomic ganglia and in the central nervous
sys tem.
E. When the high intracellular [Ca2+] dur ing an ac t ion potent ial is lowered again towards the res t ing
level, the cell c ontrac ts . This is accomplis hed by s t imulat ion of the sarcolemmal Ca2+pump, and
by blockade of both Ca2+ input and Ca2+ release.
Try to solve the problems before look ing up the answers.
H i g h l i g h t s
Rec ruitment is the inc rease in force and contrac t ion veloc ity of a musc le by ac t iv at ion of more
and more motor units .
Synaptic trans fer refers to the transmiss ion of s ignals from one neuron to another , and the s ite
of contac t between the two neurons is called the s ynapse.
A chemical s ynapse cons is ts of a neuronal presynaptic terminal, a s ynaptic c left and a
subsynaptic membrane with assoc iated receptor proteins . The chemical s ynapse is highly
developed in the CNS. I t c onduc ts the s ignal one way only , and has a charac ter is t ic s ynaptic
delay .
A gap junc t ion or elec tr ic al s ynapse is a pathway of low elec tr ic al res is tance that connec ts
cy toplasm of adjacent cells . A junc t ion couples adjacent cells elec tr ic ally and thus allows
synaptic transmiss ion without delay .
Neurons with motor func t ion have the ability to s ynthet iz e acety lcholine, because they contain
cholineacety ltrans ferase.
GABA (gammaaminobuty r ic ac id) in the brain and gly c ine in the spinal c ord are inhibitory
neurotransmitters . Binding of GABA to the GABA receptor opens the pore for Cl inf lux , whereby
the subsynaptic cell membrane hyperpolar iz es . The GABA receptor has a major inhibitory role in
brain func t ion and is the binding s ite for barbiturates (used in anaes thes ia) and for
benzodiazepines (used towards anx iety ) .
G lutamate, aspar tate and related ac idic amino ac ids are the mos t impor tant exc itatory
transmitters in the brain and spinal c ord. Exc itatory neurons possess exc itatory amino ac id
(EAA) receptors . These EAAmediated s ynapses predominate in the CNS.
Each neuron in the CNS is in contac t with up to 105 presynaptic axon terminals . Synaptic inputs
are integrated by either spat ial or temporal s ummation.
Neuropeptides are built by a sequence of amino ac ids . Neuropeptides are s ynthes ized in the cell
bodies of the neurons and transpor ted to the terminal buttons by rapid axonal transpor t.
Loss of dopaminecontaining neurons in subs tant ia nigra results in lac k of dopamine at the D2
receptors of the s tr iatal neurons . These neurons degenerate in Park inson´s disease caus ing
muscular r igidity and hand tremor .
Blockade of the presynaptic D2 receptors in subs tant ia nigra with ant ips ychot ic drugs reduces
K+outf lux and inc reases dopamine produc t ion and release.
The c rossbr idge c yc le theory s tates that there are mult iple c y c les of myos inhead attachment
and detachment to ac t in dur ing a musc le contrac t ion. When myos in binds to ac t in, an ac tomyos in
complex is formed with an ex tremely ac t iv e ATPase.
Musc le power or work rate is the produc t of musc le force (after load in N) and shor tening veloc ity
(m s 1) . The max imal work rate of human musc les is reached at a contrac t ion veloc ity of 2.5 m s
1 . The max imal work rate is thus (300 kPa *2.5 m s 1) = 750 kW per square meter of c ross
sec t ional area.
Tetanus is a prolonged musc le contrac t ion maintained by the prolonged Ca2+ inf lux caused by a
high s t imulat ion frequency .
Smooth musc le cells are frequently involved targets in diseases such as hyper tens ion, s troke,
as thma, and many gas trointes t inal diseases .
Smooth musc le cells maintain large forces almos t cont inually at ex tremely low energy cos ts . The
same tens ion or tone is maintained for days in smooth musc le organs ( intes t ine, ur inary bladder ,
and gall bladder ) .
Myocardial c ells form an elec tr ic al s yncy t ium in the same way as the smooth musc le cells do.
Myocardial c ells depr iv ed of oxygen for 30s cease to contrac t.
The mos t impor tant smooth musc le disorders are as thma and hyper tens ion.
The mos t impor tant myocardial disorders are coronary ar tery disease, ar rhy thmias , and chronic
hear t disease.
Myas thenia grav is is a disorder of neuromuscular contrac t ion. The pat ients frequently have an
inc reased blood concentrat ion of ant ibodies agains t their own acety lcholine receptor protein and
thymic hyperplas ia.
Duchenne muscular dys trophy is an X linked recess ive musc le disorder charac ter iz ed by the
absence of dys trophin in the s tr iated musc les and in the myocardium.
Further ReadingKupfermann, I . "Func t ional s tudies of c otransmiss ion." Phys iol. Rev . 71: 683, 1991.
Pollac k , G .H. "Musc les and molecules : Uncover ing the pr inc iples of biological motion." Seatt le,
Washington, 1990. Ebner & Sons .
Alber ts , B. et al. "Molecular biology of the cell." 4th Ed. , 2002, Gar land Publis hing, Inc ., New
York & London.
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