Skeletal Muscle from Molecules to Movement. A Textbook of Muscle Physiology for Sport, Exercise, Physiotherapy and Medicine

196 Pages·2004·5.66 MB·English

by  David Jones

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Preface
Muscle is an important, interesting and popular factual,basedonthematerial inthatchapter,others
subject for students from a range of disciplines refer back to previous chapters and others refer
includingmovementsciences,sportscience,phys forward. For a few questions there is no correct
iotherapy, biochemistry and medicine, and it is answer, only speculation, and we hope these will
ourexperienceofteachinginallofthese areas that illustratethelimitationsofourknowledgeand the
has led us to produce this book. It is intended to needforfurther research.
provide an accessible source of basic information The figures and illustrationsare reproduce here
aswell asan introductiontoa numberofareas of in black and white or as halftones with the inten
research interest. Chapters1-6 and15providethe tion ofkeepingthe costofthebooktoaminimum
groundwork,coveringstructureandfunction,bio and making it affordable for all. However, colour
chemistry and the mechanism offorcegeneration certainly enhances illustrations, especially histol
and we hope that this will be useful both for ogysections,andwehavetherefore includedaCD
students coming new to the subject or for those with all the illustrations in their original colours
who wishtorevise andbebroughtup todate. The and hope that this will complement the mono
other chapters deal with topics where there is chrome text.
controversy and speculation and we have tried It is said that you never understand a subject
to summarize the current state of knowledge, until you come to teach it and this is even truer
topointoutwhatiswellestablished,whatisspec whenitcomestowritingabooksuchasthiswhere
ulative and where current research is leading. we have continued to debate and refine the text
These latter sections reflectourowninterests and even to the final proofstage. In writing this book
research and, hopefully, also our enthusiasm for we have learned a lot and hope that we can pass
thesubject. thisknowledgeon tonewgenerationsofstudents.
The learning process is complex and requires
more than a passive downloading of facts. DavidJones
Consequentlywehaveaddedaseriesofquestions Joan Round
at the end of each chapter to stimulate a more ArnolddeHaan
active learning process. Some ofthe questions are August 2003
Acknowledgements
Agreatdeal of the material in this book isbased Tony Sargeant for their support, encouragement
on research carried out with close colleagues andlively debateoverthe years. One ofuswould
and the references in the text indicate the impor also like to remember David Hill who was a
tance to us of these collaborations. In particular major influence at a time when he (DAJ)was just
we would like to thank Richard Edwards and starting totake an interestinmusclephysiology.
Abbreviations
ACh acetylcholine MEPP miniatureend-platepotential
AChR acetylcholinereceptor MHC myosinheavychain
A-CSA anatomicalcross-sectionalarea MLC myosinlightchain
ADP adenosinediphosphate mRNA messengerribonucleicacid
AMP adenosinemonophosphate MRS magnetic resonancespectroscopy
ATP adenosinetriphosphate MVC maximumvoluntarycontraction
BCAA branched-chainaminoacid NAD(H) (reduced) nicotinamide-adenine
CGRP calcitoningene-relatedpeptide dinucleotide
CK creatinekinase NADH-TR NADHtetrazolium reductase
CoA coenzymeA NMJ neuromuscularjunction
CPT carnitinepalmitoyltransferase P phosphate
DHP dihydropyridine PCr phosphocreatine
DMD Duchennemusculardystrophy P-CSA physiologicalcross-sectionalarea
DOMS delayed-onsetmusclesoreness PDH pyruvatedehydrogenase
EC excitation-eontraction(coupling) (complex)
EDTA ethylenediaminetetra-aceticacid PFK phosphofructokinase
EM electronmiscroscopy Pi inorganic phosphate
EMG electromyography PTP post-tetanicpotentiation
FAD(H2) (reduced) flavin-adenine SCI spinalcord injury/injured
dinucleotide SDH succinatedehydrogenase
GABA -y-aminobutyric acid SMA spinalmuscularatrophy
GTP guanosinetriphosphate SR sarcoplasmicreticulum
HIF hypoxia-induciblefactor SREC short-rangeelastic component
IMP inosinemonophosphate SSRI selectiveserotonin-reuptake
IP inositol l,4,5-triphosphate inhibitor
3
IV internationalunit TCA tricarboxylicacid
ME myalgicencephalopathy Tm tropomyosin
CHAPTER CONTENTS
Thecontractileproteins
Actin 2 Structure of the
Myosin 2
muscle fibre
Structuralproteins 4
Sarcoplasmicreticulum 5
Ttubularsystem 5
ThemyofibrilInrelationtothefibre
andmuscle 6
Muscleorganization 6
Referencesandfurtherreading 8
Questionstothinkabout 8
Oneof the majordifferences betweenplants and
animals is that, whereas green plants can obtain
energy from sunlightand nutrients from the soil
they grow in, animals have to forage for food or
prey. Purposeful movement is, therefore, char
acteristic of higher animals, and this function
requires the activityofvoluntaryskeletalmuscle.
The consequences of skeletal muscle activity are
very evident-be it in the gentle movements of
quietbreathingor the moredramaticendeavours
ofan athlete sprintingor jumping. Muscleisone
ofthe few tissuesin whichitispossibletounder
stand, at the molecularlevel, how these verydif
ferent actions take place and are regulated. The
main purposes of this and following chapters is
to explain the link between molecular mech
anisms and the function of the whole muscle
workingin the body.
Oneofthereasonswhysomuchisknownabout
the molecular mechanisms underlying function
inskeletal muscle isbecauseofthe highlyordered
structure ofthe contractileelements. The descrip
tion that follows begins with the contractile
proteins, explains how these are arranged into
sarcomeres and myofibrils within muscle fibres,
and how the fibres then combinewithconnective
tissue toform the wholemuscle.
THE CONTRACTILE PROTEINS
Although deliberate movement is one of the fea
tures thatseparatesanimalfrom plantlife,never
thelesscontractileproteins,bothmyosinandactin,
are found in all types of cell, being responsible
for protoplasmic streaming and movement of
2 SKELETALMUSCLE FROMMOLECULES TOMOVEMENT
intracellularorganelles. Actinisaproteinofgreat simple, giving athin Zline,whereasinslow fibres
antiquityandishighly conservedinthesensethat there may beseveral connectionsbetweenthe two
actinsfromanimalandplantcellsarefunctionally sets of thin filaments, giving a thicker Z line (see
and immunologicallysimilar.Skeletalandcardiac Figs4.12& 11.1).
muscle are unusual, not for possessing actin and
myosin, but for their particularly high content
Myosin
(about 80%oftotal protein),andforhaving these
two proteins arranged in a highly ordered array Aswith actin,myosin isfound inanimal andplant
within the cell, permitting the controlled gener kingdoms, the variety found in mammalian skel
ation offorceandmovement. etal muscle being known as myosin II.The mole
cule consists of two identical chains, each with a
Actin molecular weight of approximately 200000, to
gether with four light chains of around 20000
Actinisaglobularprotein(G-actin)withamolecu molecular weight each (for reviews see Rayment
lar weight of 42000, which polymerizes into et al 1993a,b). In mollusc muscle the myosin light
double helical strands (F-actin) (Fig. 1.1). The chainshaveaclearregulatory role,bindingcalcium
polymerization of actin involves splitting ATP and controllingtheactivityofmyosin.Mammalian
and binding of ADp, which constitutes about lightchainscansubstituteformollusclight chains,
90%of the total ADP in muscle. The actin fila demonstrating that they have functional potential
ments (also known as thinfilaments) are variable but, todate, no unequivocal rolefor these proteins
inlength, with mammalianfilaments beingsome hasbeenfound.Thecompositionofthelightchains
whatlongerthanthose ofamphibianmuscle. The differsbetweenfastand slowmuscles.
thin filament length also varies between muscles The myosin molecule can be split into two
in the same animal and even within a sarcomere major fragments (Fig. 1.2A).The globular head,
sothat theedgeoftheIband (seeFig.1.4)may be
somewhat irregular. Tropomyosin and the three
troponin molecules, TnC, TnT and TnI, form the
other constituents ofthe thin filaments (Fig.1.1).
The tropomyosin extends over seven actin sub
units,blocking thesiteswheremyosincanbindto
the thinfilament until causedtomoveby calcium
bindingtotroponinC.
The actin filaments join at one end to form the
Z-linestructure. At the Z line, the actin filaments
are in a square array, with each thin filament in
onehalf-sarcomere being linked tofour other fila
ments in thenext half-sarcomere, withthe protein
o-actinin forming the connections between the
actinfilaments.Infastmuscles,thelinkage isquite
Figure1.2 Myosinstructure and assembly intothick
filaments. A, schematic arrangementofmyosinsubunits
showingthe S1andS2portions ofthe molecule andthe
regulatory (RLC)andessential (ELC)lightchains.B &C,
Figure1.1 Partofanactinfilament together with the basicdouble-headedmyosinunitsaggregating toform
tropomyosinandtroponin (Tn). athick filament.
STRUCTUREOFTHE MUSCLE FIBRE 3
or 51fragment, contains the ATPaseactivity and the thin filaments are held in a square array,
isthe portionthatcan combinewithactin. The 52 whereasinthe overlapregiontheyareforced into
portion includes the flexible region of the mol a hexagonal array by the arrangement of the
ecule and a tail, which combines with other tails, thick filaments. The thin filaments must, there
bindingthemyosinmolecules togethertoformthe fore, be somewhat flexible and in the I-band
thickfilaments (Fig.1.2B,C).Thickfilaments consist region, where there is no overlap, the actin fila
of approximately 300molecules arranged so that ments are in transition between the square and
the myosin heads are pointing in the opposite hexagonalarrayandno regularstructureisseen.
directions in the two halves of the filament. Con The nomenclature of the various bands in a
sequentlythereisaregioninthecentreofeachfila sarcomere is shown in Figure 1.4. The A and I
ment where there are only tails and no projecting bands are so called because of their birefringent
heads. This region constitutes about 10%of the propertiesunder the lightmicroscope, the Iband
totallength. Unlike the thinfilaments, which vary being isotropic and the Aband anisotropic. At a
a little, the thick filaments are very uniform in more mundane level, the bands can be remem
length throughoutthe animal kingdom. bered as being light (I)and dark (A) when seen
In the muscle fibre, thick myosin filaments are in longitudinal sections with the electron micro
arrangedsothatthe thinactin filamentscan slide scope. The area in the A band where there is no
betweenthem(Fig.1.3).Theunitfrom Zline toZ overlap with thin filaments is known as the H
line is known as asarcomereand, in mammalian zone, in the centre of which is the region of the
muscle is between 2 and 2.5J.1m long when the thick filaments bare of projecting myosin heads.
muscle isheld at its natural resting length in the Proteins running across this region give rise to
body. Each thick filament is surrounded by six the Mline (Fig.1.4).
thin filaments, so thateach myosinfilament may Identification of the two contractile proteins
bind to any of six actin filaments (Fig. 1.3). and understanding how they are arranged to
Conversely, each actin filament can interactwith give the banded appearance of skeletal muscle
three different myosin filaments. At the Z lines has been central to understanding of the mech
anism of force generation. This knowledge has
been derived, first, from observations with the
light microscope showing that the Aband isof a
constantwidth, whileitisthe Ibandthatchanges
as the muscle lengthens and contracts (see Fig.
2.1).Second, the locationofthe differentproteins
Figure1.3 Arrangementofthickand thinfilaments toform Figure1.4 The banded, orstriated, appearanceofskeletal
asarcomere. Below,cross-sectionsofthesarcomerewhere, muscle.Above, portion ofanelectron micrographoftwo
from lefttoright,there areonly actin filaments, only myosin sarcomeres;below, adiagram showing thearrangementof
filaments and,onthe right, overlap ofactin and myosin. actin and myosinfilaments.
4 SKELETALMUSCLE FROMMOLECULESTOMOVEMENT
was confirmed by experiments in which myosin template on which the myosin monomers
was extracted from dissociated myofibrils with condense to make the thick filaments. Titin also
potassium chloride solution containing ATP or helps to provide longitudinal stability to the sar
pyrophosphate, showing that, after extraction, comere, as it appears to be responsible for the
the Z line and I bands remained but the Aband resting force at long sarcomere lengths and pre
had been removed. Finally, observations at the ventsthe sarcomeresbeingpulledapart. Nebulin
electron microscopic level of the way in which is another very large protein found associated
myosin monomers in solution aggregate to form with actin near the Z line, it may strengthen the
the characteristic bidirectional filaments (Fig. thin filaments or may act as a template for the
1.2C)indicated the structure and possible func actin monomers to form filaments. The Z-line
tion ofthe thick filaments. structure contains o-actinin that binds the actin
filaments together,while desminlinks the Zlines
of adjacent myofibrils and serves to keep the Z
STRUCTURAL PROTEINS
lines in register.
There are a variety of proteins whose function Dystrophin is another very large protein, the
is to maintain the architecture of the sarcomere. function of which is to anchor the contractile
Proteins constitutingthe Mline (Fig.1.4)keep the apparatus to the surface membrane and, via
myosin filamentsinthecorrecthexagonalarrange connections with other proteins such as dystro
ment fortheactinfilaments toslidebetween. glycan, sarcoglycan and laminin, links with the
Titin isan extremely long protein(about1urn) basementmembrane (Fig.1.5).The precise func
which runs from Z line to Mline and could be a tions of these proteins are not known, but they
Figure 1.5 Cytoskeletal proteins connecting thebasement membraneand
sarcolemmawith theunderlyingcontractile structures. DG,dystroglycan;SG,
sarcoglycan-glycosylatedproteins inthesurface membrane. N,nitricoxide
synthase (NOS); ST,syntrophin that bindssignallingmolecules, such asNOS,
todystrophin and dystrobrevin.
STRUCTURE OFTHEMUSCLE FIBRE 5
are clearlyvery important as absences or defects SARCOPLASMIC RETICULUM
are associated with a range of muscle-wasting
Groups of about 200 thick and thin filaments
diseases known as the muscular dystrophies.
constituteamyofibril. Eachmyofibrilisenveloped
Duchenne muscular dystrophy and the milder
in a complex membranous bag, known as the
form of Becker dystrophy are associated with
sarcoplasmic reticulum, the interior of which is
an absence, or abnormalform, ofdystrophin(see
quite separate from the cytoplasm of the fibre
Ch. 15).This cytoskeletal complex is also associ
(Fig.1.6).Thismembranesystemisastorefor the
ated with signalling proteins and nitric oxide
uptakeandrelease ofcalcium.The portionslying
synthase, which may be involved in sensing
near the T tubules (see below) are known as the
mechanical activity, muscle length etc., leading
terminal cisternae.
tofunctional adaptations.
T TUBULAR SYSTEM
Thesurfaceorplasmamembrane(sometimesalso
known as the sarcolemma) of the muscle fibre
invaginates, forming T tubules which run trans
versely (hence their name) across the fibre, form
ing a complex branching network that contacts
and, mostly,surroundseverymyofibril(Fig.1.7).
The invaginations of the surface membrane
occur twice in everysarcomere approximatelyat
the level of the junction of the A and I bands.
In amphibian muscle, in contrast to mammalian
muscle, thereisonly oneTtubulepersarcomere,
and this runs at the level ofthe Z line. Where the
Figure1.6 Thesarcoplasmic reticulum envelopsa
myofibril. T tubules meet the sarcoplasmic reticulum, the
A B C
Figure1.7 Ttubules inr~lationtothesarcomere.Ttubules invaginatefromthe surface
membrane ofthemusclefibre (C)andcontact the myofibrils atthejunction ofthe AandI
band (A&B).
6 SKELETALMUSCLE FROMMOLECULESTOMOVEMENT
Figure1.8 Ttubules, sarcoplasmicreticulum andthe myofibrils.Structureofatriad is
shownwithinthe ring.Mit,mitochondria.
two membranes run very close to one another, sarcoplasmicreticulum,Ttubulesandsometimes
andwiththe electronmicroscopedense'feet'can mitochondria. Myofibrils vary in size but aver
beseen linking the two sets ofmembranes. age around 1urn in diameter, making up about
In electron micrographicsections, the Ttubules 80% of the volume of a muscle fibre. The num
areoftenseencutincross-sectionwithaportionof bers of myofibrils vary with the size of the
thesarcoplasmicreticulumoneitherside (Fig.1.8); muscle fibre and there may be as few as 50 in a
this is known as a 'triad'. When associated with developing fetal muscle fibre. There are about
sarcoplasmic reticulum in a triad, the T tubule 2000myofibrilsin an adultmusclefibre. Bundles
is flattened; otherwise it tends to be circular in of muscle fibres are then arranged together to
cross-section. form the anatomicalmuscle(Fig.1.9).
THE MYOFIBRIL IN RELATION TO MUSCLE ORGANIZATION
THE FIBRE AND MUSCLE
Each muscle fibre is bounded by its sarcolemma
Bundles of 100 to 400 filaments form myofibrils, or plasma membrane. At resting lengths the
which are separated from adjacent myofibrils by membrane is folded with small indentations or