Muscle

Muscle
Muscle
Muscle is composed of bundles of specialized cells

capable of contraction and relaxation to create
movement.
Muscle
There are three types of muscle in the body:
Striped, or striated,
skeletal muscles that
move the bones.
Muscle
There are three types of muscle in the body:
Smooth, involuntary
muscles that line the
blood vessels, stomach,
digestive tract, and
other internal organs.
Cardiac muscles, which

are a cross between the
smooth and the striped
muscles.
Muscle
skeletal muscles
Skeletal muscle is made up of thousands of

cylindrical muscle fibres often running all the way
from origin to insertion.
The fibres are bound together by connective tissue
through which run blood vessels and nerves.
Muscle
Each muscle fibre
contains:
An array of myofibrils
Endoplasmic reticulum
Many nuclei
Mitochondria
Muscle
Ultrastructural Organisation of
Skeletal Muscle
Contractile cells of skeletal muscle are extremely
long, multinucleated, and bound by an electrically
excitable plasma membrane called the Sarcolemma.
The myofibrils, the contractile elements, occupy a

large volume of the muscle cell.
Muscle
Ultrastructural Organisation of Skeletal
Muscle
The myofibrils are arranged in parallel bundles in the
axis of contraction; each myofibril contains many
myofilaments.
The myofibrils are surrounded and bathed by the
sacroplasma.
It contains:
glycogen, glycolytic
enzymes and intermediates,
ATP, ADP, AMP, phosphate, phosphocreatine,
creatine.
Muscle
Muscle
Muscle cells also contain highly
endoplasmic
reticulum,
referred
sarcoplasmic reticulum.
differentiated
to
as
the
Myofibrils, which are long, thin bundles of

myofilaments, have along their length a structural
pattern that repeats every 2.5 m.
These repeat units are called Sarcomeres, and are
the contractile units of the myofibrils.
Muscle
Muscle
In skeletal/striated muscle, the sarcomeres of many
parallel myofibrils are in transverse register, yielding
the characteristic cross
striations across
the muscle cell.
Muscle
Muscle
The light bands are called Isotropic or I bands.
The dark bands are called Anisotropic or A bands.
Muscle
Muscle
Isotropic structures are those that have uniform
physical properties regardless of the direction in
which they are measured.
Anisotropic structures are those that have physical
properties, which depend on the direction of
measurement.
The A bands of muscle are optically anisotropic; i.e.,
their index of refraction is not uniform in all
directions, giving them the property of double
refraction, or birefringence.
Muscle
Muscle
The I cross striations are bisected by a dense
transverse line about 80 nm thick, the Z line. The
central portion of the A band, the H zone, is less
dense than the rest of the band; it is also bisected by
a dense transverse line, the M line.
Muscle
Muscle
There are two types of myofilaments:
-thick
-thin
Only thin filaments are present in the transverse I
band.
Thin filaments of the I band and a regular array of
thick filaments are present in the dense portions of
the A band.
Muscle
Muscle
Thick and thin muscles are
approximately 45 nm apart
and are arranged in a
hexagonal pattern.
Each thick filament is
surrounded a six thin
filaments,
also
in
a
hexagonal array.
Muscle
Muscle
The thick filaments extend continuously from one
end of the A band to the other.
The thin filaments are not continuous through the

entire A band.
Muscle
Muscle
The thin filaments :
- begin at the Z line
- are continuous through the I bands
- extend into the A bands, terminating at the end of
the H zone of the A bands.
Regularly disposed projections extending from the
thick filaments toward adjacent thin filaments form
cross bridges, which represent the only structural
connection between the thick and the thin filaments.
Muscle
The Sarcomere during Contraction
When maximally contracted, the Sarcomere may
shorten between 20 and 50%. When passively
stretched, they may extend to about 120% of their
resting length.
The A bands, and thus the thick filaments always
remain constant in length in the relaxed, contracted
and stretched states.
The thin filaments likewise undergo no change in
length.
HOW DOES THE SARCOMERE CONTRACT?
Muscle
When muscle undergo maximal shortening, the thin
filaments may even slide pass each other to form a
new, dense central band within the H zone.
Muscle
Cross bridges are therefore rapidly formed and
broken as filaments slide over each other.
The Sliding-Filament Model.
The actin (thin) filaments slide past the myosin
(thick) filaments toward the middle of the
sarcomere.
The result is shortening of the sarcomere without
any change in filament length.
Muscle
The Protein Components of Muscle
Muscle cells consist of various intracellular proteins:
The water-soluble proteins of the sarcoplasm, which
make up about 20 to 25% of the total muscle
protein.
water-insoluble
myofibrils.
filamentous
proteins
of
the
Myogen is present in the water-soluble proteins and

is rich in glycolytic enzymes, and from it the
enzymes aldolase, glyceraldehydye-phosphate, etc.
Muscle
The Protein Components of Muscle
Myosin as well as actin is present in the waterinsoluble filamentous proteins. They make up
approximately 80% of the proteins of the
contractile apparatus.
In addition there are at least six other protein
components:
Tropomyosin
Troponin
C-protein
M-line protein
- and -actinin
Muscle
Myosin
It has been suggested that the myosin fraction is a
major component of the anisotropic bands of
skeletal muscle.
Myosin is also the major component of the A bands,
thick muscle filaments.
Myosin is highly asymmetrical, molecules tend to
associate tightly with each other and with other
myofilament proteins, a property that gives the
illusion of homogeneity.
Muscle
Myosin
It has a molecular weight of 460 kDa, it is long
(approx. 160 nm) and asymmetrical containing a
globular head.
The molecule contains a globular head with two
identical long polypeptide chains of approximately
200 kDa, called the heavy chain.
Myosin contains three unusual amino acids, 3methylhistidine, -N-monomethyllysine, and -Ntrimethyllysine.
Muscle
Myosin
The head contains four smaller or light polypeptide
chains.
Two of the light chains are identical and have a
molecular weight of about 18 kDa.
The two other light chains are about 16 kDa and 21
kDa.
Through most of the length of the myosin molecule,
each heavy chain is in -helical conformation and
the two chains are wound around each other.
Muscle
Myosin
Both the heavy polypeptide chains are folded into
globular structures to form the head.
Highly purified myosin preparations can hydrolyse
the terminal phosphate group of ATP. The ATPase
activity of myosin is distinctive in that:
It is stimulated by Ca2+,
It is inhibited by Mg2+,
It
is
profoundly
influenced
by
KCl
concentration,
It has two pH optima, one at pH 6.0 and the
other at pH 9.5.
Muscle
Myosin
Myosin
ATPase
activity
is
characteristically
dependent on two different sulfhydryl groups, which
differ in their susceptibility to alkylation or to
mercaptide formation.
When the more susceptible SH groups are blocked,
the ATPase activity of the myosin molecule is
increased.
When the second class of sulfhydryl groups is then
blocked, the ATPase activity is abolished, suggesting
that these SH groups are required for the hydrolytic
process.
Muscle
Myosin
When
myosin
is
exposed
to
trypsin
and
chymotrypsin heavy and light meromyosin are
produced, HMM and LMM respectively.
Muscle
Myosin
LMM, like myosin, forms filaments.
HMM, catalyzes the hydrolysis of ATP and binds actin
but does not form filaments.
HMM is the
contraction.
force
generating
unit
in
muscle
HMM can be further cleaved to two globular

subfractions (S1) and one rod-shaped subfraction
(S2).
Muscle
Myosin
Each S1 fragment contains an ATPase site and a

binding site for actin.
Muscle
Myosin
The ATPase activity of the myosin molecule resides
entirely in its head and that there are two catalytic
sites, one in each of the two S1 fragments.
Each contains an inhibitory and a catalytic sulfhydryl
group.
The light chains in the myosin heads are concerned
with the binding of ATP and in the ATPase activity.
Purified, intact myosin binds actin at two specific
sites to form actomyosin, a crucial step in the
contractile mechanism.
Muscle
Myosin
Whereas the ATPase activity of pure myosin requires
Ca2+ and is inhibited by Mg2+, the ATPase activity of
actomyosin is stimulated by Mg2+.
The entire actin-binding activity of myosin resides in
the S1 fragments bearing the ATPase activity, and
the two catalytic ATPase sites on the head of the
myosin molecule are located at or near the actin
binding sites.
Muscle
The Mechanism of Myosin ATPase
Activity
Three different enzyme-substrate complexes, noncovalent in nature, are formed during the ATPase
activity of myosin.
When equimolar amounts of ATP and myosin are
mixed, there is a very rapid appearance of free H+ in
the medium but a much slower appearance of free
phosphate and ADP. The H+ arises as one of the
products of hydrolysis of ATP at pH near 7.0:
ATP4- + H2O ADP3- + HPO42- + H+
Muscle
Activity
Various hypotheses have been proposed for the
mechanism of myosin ATPase activity.
A simple version is (M- Myosin and M* - energized
conformation of myosin):
M + ATP
rev MATP
MATP + H2O
M*ADPP
MADPP
rev M*ADPP + H+
MADPP
rev M + ADP + P
Muscle
Activity
The M*ADPP is postulated to be a high-energy
complex, in which the free energy of hydrolysis of
ATP is conserved in the form of an energized
conformation of the myosin molecule.
The energy-releasing reaction has been proposed to
be responsible for the power stroke in contraction.
The ATPase activity of myosin is markedly increased
by actin. Actin has a capacity to activate ATP
hydrolysis by myosin.
Muscle
Activity
It increases the turnover
number of myosin 200-fold,
from 0.05s-1 to 10s-1 by
binding
to
the
MADPP
complex and accelerate the
release of the products.
Actomyosin then binds ATP,
which leads to the dissociation
of actin and myosin.
Muscle
Organisation of the Thick Myofilaments
Muscle
Each thick filament is about 1,500 nm long and 10
nm thick.
It consists of longitudinal bundled myosin molecules,
each 160 nm long.
The myosin molecules are oriented with their heads
away from the midpoint of the thick filaments.
The heads project laterally out of the bundle in a
regular, helical fashion.
Muscle
In a cross section of the thick filaments at any given
point there are 18 myosin molecules in a regular
packing arrangement.
Altogether there are
approximately 400 myosin
molecules per complete
thick filament.
The myosin heads, which
resemble barbs, vary in
the distance they project
from the thick filament.
Muscle
Each myosin head is located next to the hinge-like
trypsin-sensitive point.
Thick filaments also contain two other proteins,
namely, C-protein (140 kDa, 3.5% of thick filament
protein, binds very strongly to myosin tail, 35 nm
long and wound around the thick filament at regular
intervals) and M-line protein.
Both may serve to hold the bundle of myosin
molecules together.
Muscle
Actin
Evolution has not changed the Actin genes much
such that Actin from different species is found to be
often interchangeable in in vitro assays.
This protein is the major component of thin
filaments and occurs in two forms, G-actin (globular
actin) and F-actin (fibrous actin), a polymer of Gactin.
Muscle
Actin
They are the principal components of the thin
filaments in skeletal muscle.
They have a polar structure and this polarity from
one end to the other is crucial for cell motility.
G-actin contains an unusual amino acid
methylhistidine, which is also present in myosin.
3-
It also contains a large number of proline and

cysteine residues.
Muscle
Actin
Each molecule of G-actin binds one Ca2+ ion very
tightly. It also binds one molecule of ATP or ADP with
high affinity.
For each molecule of G-actin added to the F-actin
chain, one molecule of ATP is split to ADP and
phosphate.
The ADP formed remains bound to the G-actin
subunit of the F-actin chain.
n{G-actin-ATP} {G-actin-ADP}n + nPi
F-actin
Muscle
Organisation of the Thin Filaments
Two strands of F-actin each composed of Gactin monomers are coiled about each other
in the thin filament.
The thin filaments also contain two major
accessory proteins, which serve a regulatory
function in controlling the making and
breaking of the cross bridges between the
thick and thin myofilaments, as well as the
generation of mechanical force.
Muscle
The first is Tropomyosin (70 kDa with two
helical chains of 33 kDa and 37 kDa, which
form a two-chain twisted coil of about 40 nm
long), which makes up 10 to 11% of the total
contractile protein of muscle.
They are long, thin, and arranged end to end
in the shallow grooves of the coiled F-actin
filaments, in such a way that each
tropomyosin molecule makes contact with
only one of the two F-actin filaments.
Muscle
The second is Troponin, which is a large
globular protein that contains three
polypeptide subunits:
The Ca2+ binding subunit of troponin (TNC, or troponin A).
The inhibitory subunit of troponin (TN-I).
It has a binding site specific for actin but it
does not bind Ca2+.
3.Tropomyosin-binding
troponin (TN-T).
subunit
of
Muscle
The complete troponin molecule contains one
each of the TN-C, TN-I, and TN-T subunits
and has a globular shape.
Each troponin molecule is attached to the thin
filament by two binding sites, one specific for
an actin strand and the other for a
Tropomyosin strand.
For every seven G-actin monomers there is
one molecule of tropomyosin and one of
troponin.
Muscle
Actomyosin complexes
When pure myosin and actin are mixed,
actomyosin complexes are formed, which
results in increased viscosity and flow
birefringence.
The ratio of myosin to actin and the particle
weight of such actomyosin complexes depend
on the experimental condition, such as:
pH, the KCl and MgCl2 concentrations, as well
as the protein concentration.
Muscle
Since an F-actin chain
contains many G-actin
monomers, each F-actin
filament can bind many
myosin molecules,
however, only the heads
of myosin molecules
bind to the actin
filaments to yield
structures resembling
barbs.
Muscle
A
significant
property
of
actomyosin complexes is that
they undergo dissociation in
the presence of ATP and Mg2+;
the dissociation is accompanied
by a large and rapid decrease
in
the
viscosity
of
the
actomyosin solution.
When
ATP
is
completely
hydrolyzed to ADP, the actin
and myosin re-aggregate.
Muscle
Ca2+ Triggers Thick-Filament-ThinFilament Interaction and the
Generation of Force
In the relaxed state, the sarcoplasm has a high
MgATP2- concentration, but the concentration of Ca2+
is below the threshold required for initiation of
contraction.
The myosin heads are in a contracted state. Each
head in this state contains two molecules of tightly
bound ATP.
The ATP maybe present as ADP and phosphate, both
tightly bound to the energized conformation of the
myosin head.
Muscle
Ca2+ Triggers Thick-Filament-Thin-Filament
Interaction and the Generation of Force
The myosin head in this state is unable to react with
actin of the thin filaments because in the absence of
Ca2+ the Tropomyosin molecule masks the myosin
binding site on the G-actin monomer or holds it in a
conformation that is un-reactive, through the action
of the TN-I subunit of troponin.
When free Ca2+ is now released into the sarcoplasm
by the incoming nerve signal, Ca2+ is immediately
bound to the Ca2+-binding sites of troponin.
Muscle
Through a conformational change of the troponin
molecule, the myosin-binding site of the G-actin
monomer now becomes exposed and combines with
the energized myosin head, with its bound ADP and
phosphate,
to
form
the
force-generating
complex, in which the myosin head is attached to a
G-actin monomer.
Muscle

The myosin head is now believed to undergo an
energy-yielding conformational change, so that the
cross bridge changes its angular relationship to the
axis of the heavy filament, causing the thin filament
to be moved along the thick filament; this is the
power stroke.
Muscle
The Source of Energy for Muscular
Contraction
The musculature of an adult man in the resting state
utilizes approximately 30% of the total ATP energy
generated by respiration.
During very intense muscle activity, the muscles
consume 85% or more of the total ATP generated.
The high-energy Phosphocreatine is present in
muscle in about 5 times the concentration of ATP.
Muscle
Contraction
Phosphocreatine + ADP
rev creatine + ATP
ATP formation is favoured at the expense of

phosphocreatine.
This
explains
why
ATP
concentration in muscle does not decline during a
single contraction.
If the muscle is stimulated long enough in the
absence
of
glycolysis
or
respiration,
the
phosphocreatine supply will eventually become
depleted.
Muscle
Contraction
The ultimate source of metabolic energy for rephosphorylation
of
ADP,
and
thus
of
phosphocreatine, is not identical in all muscles.
Although all muscles of vertebrates show both
glycolytic and respiratory activity, the relative
contribution of glycolysis and respiration to the
regeneration of ATP from ADP may vary
considerably.
Muscle
Contraction
There are two types of skeletal muscle fibres, red, or
slow fibres and white, or fast fibres.
In red muscles, which owe their colour to their high
content of myoglobin and cytochromes, respiration
serves as the chief source of energy for rephosphorylation
of
ADP
via
oxidative
phosphorylation.
Red muscles contract more slowly than white
muscles and normally function in regular periodic
cycles.
Muscle
Contraction
White muscles, on the other hand, contain little
myoglobin and few mitochondria; in such muscles
glycolysis is the chief source of energy for rephosphorylation of ADP.
In general, red muscles use fatty acids as their
major fuel, which they oxidize via the fatty acid
oxidation cycle to acetyl-CoA; the latter is oxidized
to CO2 via the TCA cycle.
White muscles, on the other hand, use glucose as
major fuel.
Muscle
Contraction
The rates of glycolysis and respiration, and thus of
ATP production, are adjusted to the rate of ATP
consumption in muscle by a series of feedback
controls.
In resting muscle the [ATP]/[ADP][Pi] ratio is high.
Here the rates of glycolysis and the TCA are low,
because of allosteric inhibition by negative modular
ATP.
Muscle
Contraction
When the muscles are stimulated to maximal
activity, the [ATP]/[ADP][Pi] ratio is on decline with
an increase in fuel and oxygen consumption.
Oxygen uptake by skeletal muscles increased twenty
fold.
Some of the ADP formed on contraction undergoes
conversion to AMP, which stimulates glycolysis.
Muscle
Contraction
During maximal muscular exertion lactate appears in
the blood in large amounts resulting in the
consumption of considerably extra oxygen.
This extra oxygen consumed is called the oxygen
debt and corresponds to the oxidation of some or all
the excess lactic acid.
Some of the lactic acid accumulated in the blood
may be converted to glycogen by the liver.

Muscle

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Muscle

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Muscle

Muscle is composed of bundles of specialized cells

Cardiac muscles, which

Skeletal muscle is made up of thousands of

The myofibrils, the contractile elements, occupy a

Myofibrils, which are long, thin bundles of

The thin filaments are not continuous through the

Myogen is present in the water-soluble proteins and

HMM can be further cleaved to two globular

Each S1 fragment contains an ATPase site and a

It also contains a large number of proline and

Ca2+ Triggers Thick-Filament-Thin-Filament

rev creatine + ATP

ATP formation is favoured at the expense of

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