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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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