Nerve and muscle physiology

1. Leak channels or pores – always open (Resting Membrane Potential)
2. Gated channels which open and close
 Chemically (or ligand)-gated channels – open with binding of a specific
neurotransmitter (the ligand) (graded potential)
 Mechanically-gated channels – open and close in response to physical
deformation of receptors (graded potential)
 Voltage-gated channels – open and close in response to changes in the
membrane potential (action potential)
Types of plasma membrane ion channels

Membrane potential
• Separation of opposite charges
across the membrane
Or
• Difference in relative number of
cations and anions in the ECF
and ICF
• Separated charges create
the ability to do work
• Membrane potential is
measured in millivolts
• 1mv = 1/1000 volts
Which has the greatest membrane potential?

• Plasma membrane of all living cells has
a membrane potential (polarized
electrically)
• Due to differences in concentration and
permeability of key ions ie Na+ K+ and
large intracellular proteins in ICF
• Nerve and muscle cells
• They are Excitable cells
• Have ability to produce rapid, transient
changes in their membrane potential
when excited which serves as electric
signals

Resting membrane potential (RMP)
• Constant membrane
potential present in cells of
non excitable tissues and
excitable tissues when they
are at rest (not excited)
• The ions primarily
responsible for the
generation of resting
membrane potential are
Na+ & K+
• The concentration
difference of Na+ and K+
are maintained by the Na+
K+ pump.
TYPE OF CELL RMP
SKELETAL MUSCLE - 90 mvs
SMOOTH MUSCLE - 60mvs
CARDIAC MUSCLE - 85 to - 90 mvs
NERVE CELL - 70 mvs

More permeability of K+ as compared to Na+
in resting state
•The plasma membrane is more permeable to K+ in resting
state than Na+ because the membrane has got 100 times
more leak channels for K+ than for Na+
•Moreover the hydrated form of K+ is smaller than the
hydrated form of Na+

Key point
•Concentration gradient for
K is towards outside and
for Na is towards inside
but the electric gradient for
both of these ions is
towards the negatively
charged side of the
membrane

Causes of generation of RMP
1. Only 20% of the RMP is directly generated by
Na K pump
2. 80% of the RMP is caused by the passive
diffusion of Na and K down the concentration
gradient through leak channels

Plasma membrane
ECF ICF
Concentration
gradient for K+
Electrical
gradient for K+
EK+ = –94mV
EffectofmovementofK+aloneon
RMP(K+equilibriumpotential)

•.•MEMBRANE POTENTIAL CAUSED BY DIFUSION OF K IONS = -94 MV (K+
equilibrium potential)
•Nernst equation:
•Used to calculate the equilibrium potential caused by single ion.
•EMF= ± 61 Log conc. outside
____________
Conc. Inside
The potential at which no further net diffusion of ion occurs down the
concentration gradient due to equal and opposite electrical gradient is called
Nernst potential or equilibrium potential

•Therefore : for K+ ion
•EMF= ± 61 log conc. of K+ Outside
____________
conc. of K+ inside
EMF = ± 61 log 4
140
= 61 log 1
35
= 61 × 1.54 because log of 1/35 is 1.54
= -94 mvs

Plasma membrane
ECF ICF
Concentration
gradient for Na+
Electrical
gradient for Na+
ENa+ = +61 mV
EffectofmovementofNa+aloneon
RMP(Na+equilibriumpotential)

•Similarly for Na ions
•EMF = ± 61 log conc. Outside
______________
conc. Inside
= 61 log 140/14 (log of 10=1)
= 61 × 1 = + 61 mvs
• Ions with highest permeability or conductance at rest
will make the greatest contributions to the resting
membrane potential
• K is more permeable at rest so highest contribution by K
and least by Na.

Goldman equation:
Used to calculate the equilibrium potential of 2 or more ions
Therefore combining the equilibrium potential of K (-94) & Na
(+61) = - 86 mVs

Role of Na K ATPase in creating &
maintaining the RMP
• Two contributions of this pump
1. Direct electrogenic contribution of Na K pump by
pumping 3 Na out and 2 K in since more +ve ions move
outside so causes negativity of -4 mvs on inside (creating)
2. Indirect contribution is in maintaining the
concentration gradient for K across the cell
membrane, which is then responsible for the K
diffusion potential that derives the membrane
potential toward the K equilibrium potential.

NET RMP
• Net RMP = - 86 - 4 = -90mvs
• This means when the cell is at rest it has negativity of -90 mvs
inside i.e. inside the cell there is 90 mvs more negative as
compared to outside the cell

Electrical signals:
Graded potential and Action potential
• In excitable cells changes in ion movement
in turn are brought about by changes in
membrane permeability in response to a
triggering agent or a stimuli

The stimulus:
It is an external force or event which when applied to an excitable tissue
produces a characteristic response. Examples of various types of stimuli
are:
1)Electrical: use to produce an action potential in neurons .
2)Hormonal: hormones are released i.e. adrenaline act on heart to
increases its rate
3)Thermal: stimulation of thermal receptors in skin by hot or cold
objects.
4)Electromagnetic receptor: stimulation of rods & cone of retina by
light.
5)Chemical: stimulation of taste receptors on the tongue
6)Sound: stimulation of auditory hair cells

Electrical signals are produced by changes in ion
movement across the plasma membrane
• Triggering agent (stimulus)
• Change in membrane permeability
• Alter ion flow by opening and closing of gates
• Membrane potential fluctuates
•Two types of electrical signal generated ie
graded potential and action potential

Terminologies Associated with Changes in Membrane Potential
• Polarization- other than 0
• Depolarization- membrane
potential less negative than RMP.
• Overshoot- when the inside of the
cell becomes +ve due to the
reversal of the membrane potential
polarity.
• Repolarization- returning to the
RMP .
• Hyperpolarization- membrane
potential more negative than RMP.

Ion Channels
• Non-gated
• Always open
• Gated
• Open or close in response to stimuli
• Chemical (ligand)
• Electrical (voltage)
• Mechanical
• When gated channels are open:
• Ions move quickly across the
membrane
• Movement is along their
electrochemical gradients
• An electrical current is created
• Voltage changes across the
membrane
Leaky channels
Gated channels

• Three parts
• Cell Body or Soma: contains the nucleus & is the
metabolic center of neuron
• Dendrites: receptive regions; transmit impulse to cell
body
• Axon: transmit impulses away from cell body
Structure of Neuron

Parts of a Neuron: Axon
• Initial Segment: Initial 50-100 um area
after axon hillock is most excitable part;
rich in Voltage gated Na channels; site
where AP generates so called trigger zone
• Once AP generated it always propagates
towards axon terminals
• Branches at its distal end into many axons
terminals at end of which is an enlarged
area synaptic knob or button

• Short-lived, local changes in membrane potential
• Decrease in intensity with distance because ions diffusing out through permeable
membrane
• Their magnitude varies directly with the strength of the stimulus
• They can be summated
• Sufficiently strong graded potentials can initiate action potentials
Graded Potentials

Summation of graded potential
•Graded potentials occurs
at soma & dendrites &
travel through the neuron
and they sum up and if
reach a threshold level at
trigger zone they can fire
action potential.

Graded potential has different names according to
location
• Neuron cell body and dendrites
• Excitatory post synaptic potential
(EPSP)
• Inhibitory post synaptic potential
(IPSP)
• Motor end plate  End plate
potential
• Receptor  Receptor potential
• Pace maker potential in GIT
smooth muscle & heart
• Slow wave potential

Action Potentials (APs)
The AP is a brief, rapid large change
in membrane potential during which
potential reverses and the RMP
becomes +ve & then restored back to
resting state
APs do not decrease in strength with
distance so serve as long distance
signals.
Events of AP generation and
transmission are the same for skeletal
muscle cells and neurons

Initiation of action potential
• To initiate an AP a triggering event causes the
membrane to depolarize from the resting
potential of -90 mvs to a threshold of -65 to –
55 mvs .
• At threshold explosive depolarization occurs.
(positive feed back)
An AP will not occur until the initial rise in
membrane potential reaches a threshold level.
This occurs when no. of Na+ entering the cell
becomes greater than the no. of K+ leaving the
cell.

Voltage gated channels- responsible for AP
•Action potential takes place as a result of
the triggered opening and subsequent
closing of 2 specific types of channels
Voltage gated Na+ channels
Voltage gated K+ channels

Voltage gated Na+ channels
• Most important channels during AP
• It has two gates and 3 states
• Activation gates outside & inactivation
gates inside
1. At RMP activation gates are closed so
no Na+ influx at RMP thru these
channels
2. Activation gates open at threshold
3. The same increase in voltage that
open the activation gates also closes
the inactivation gates but closing of
gates is a slower process than
opening so large amount of Na+
influx has occurred
4. Inactivation gate will not reopen until
the membrane potential returns to
or near the original RMP.
Local anesthetics like lidocaine, procaine, tetracaine
block voltage gated Na channels so block the
occurrence of action potential

Voltage gated K+ channel
• During RMP Voltage gated K+ channels
are closed
• The same stimulus which open voltage
gated Na+ channels also open voltage
gated K+ channel
• Due to slow opening of these channels
they open just at the same time that the
Na+ channels are beginning to close
because of inactivation.
• So now decrease Na+ influx and
simultaneous increase in K+ out flux
cause membrane potential to go back to
resting state (recovery of RMP)
• These channels close when membrane
potential reaches back to RMP

Phases of action potential
•Depolarization
•Repolarization
•Hyperpolarization

Role of the Sodium-Potassium Pump in
action potential
Repolarization restores the resting electrical conditions
of the neuron, but does not restore the resting ionic
conditions
Ionic redistribution is accomplished by the sodium-
potassium pump following repolarization

Increased permeability of Na channels when there is
deficit of Ca ions
• The conc. Of Ca ions in ECF has profound effect on
the voltage level at which the Na channels become
activated. Ca bind to the exterior surface of the
voltage gated Na channels protein molecule.
• So when there is a deficit of Calcium ions in the ECF
the voltage gated Na channels open by very little
increase of membrane potential from its normal very
negative level. so nerve fiber become highly
excitable .
• When Ca levels fall 50% below normal spontaneous
discharge occurs in some peripheral nerves causing
tetany. Its lethal when respiratory muscles are
involved.

Effect of hypokalemia on nerve and muscle
• Hypokalemia is decreased levels of K in blood
• Decreased K in blood causes the K concentration
gradient between ECF & ICF to increase which leads to
more negative RMP as more K leaks out of cell so
hyperpolarization occurs and membrane potential is far
away from threshold value so membrane is less
excitable
• Muscle weakness and pain
• Irregular heart beats

Effect of hyperkalemia on MP
•Hyperkalemia is increased levels of K in blood (above
5 mmol/lit)
•Elevated K in blood causes the K concentration
gradient between ECF & ICF to decrease which leads
to less negative RMP as less K leaks out of cell so
closer to threshold value so easily excitable but at
the same time prevent repolarization so Na channels
will not be activated so leading to muscle weakness
and paralysis and cardiac arrhythmias.

Propagation of Action Potential
•A single action potential
involves only a small
portion of the total
excitable cell membrane
and then the action
potential is self-
propagating and moves
away from the stimulus
(point of origin)

Conduction of Action Potentials
•Two types of propagation
• Contiguous conduction
• Conduction in unmyelinated fibers
• Action potential spreads along every portion of the membrane
• Saltatory conduction
• Rapid conduction in myelinated fibers
• Impulse jumps over sections of the fiber covered with
insulating myelin

MYELIN
• Myelin
• Most axons are myelinated.
• Primarily composed of lipids sphingomyelin
• Formed by oligodendrocytes in CNS
• Formed by Schwann cells in PNS
• Myelin is insulating, preventing passage of ions over the
membrane as it is made up of lipids so water soluble ions
cannot permeate so current cannot leak out in the ECF

• The resistance of the membrane
to current leak out of the cell and
the diameter of the axon determine
the speed of AP conduction.
• Large diameter axons provide a
low resistance to current flow
within the axon and this in turn,
speeds up conduction.
•Myelin sheath which wraps around vertebrate axons prevents current leak out of the cells. Acts like an
insulator, for example, plastic coating surrounding electric wires. It is devoid of any passage ways.
• However, portions of the axons lack the myelin sheath and these are called Nodes of Ranvier. They
are present at about 1 mm intervals along the length of axons . High concentration of Na+ channels are
found at these nodes so AP occurs only at nodes
2 ways to increase AP propagation speed

Importance of saltatory conduction
• Increases the
conduction velocity
through myelinated
nerve fiber.
• Conserves energy for
the axon
• In demyelinating diseases,
such as multiple sclerosis, the
loss of myelin in the nervous
system slows down the
conduction of APs. Multiple
sclerosis patients complain of
muscle weakness, fatigue,
difficulty with walking

Properties of Action Potentials
1. The All or Nothing Principle:
Action Potentials occur in all or none fashion
depending on the strength of the stimulus
2. The Refractory Period:
Two phases:
a) Absolute refractory period
b) Relative refractory period

All-or-None Principle
• If any portion of the membrane is
depolarized to threshold an Action potential
is initiated which will go to its maximum
height.
• A triggering event stronger than one
necessary to bring the membrane to
threshold does not produce a large Action
potential.
• However a triggering event that fails to
depolarize the membrane to threshold does
not trigger the Action potential at all.

Refractory period (unresponsive or stubborn)
•A new action potential cannot occur in an
excitable membrane as long as the membrane is
still depolarized from the preceding action
potential.

Absolute Refractory Period
• Membrane cannot produce
another Action potential no
matter how great the stimulus is.
• Last for almost entire duration of
action potential.
• Cause: closure of inactivation
gates of voltage gated Na
channels in response to
depolarization. They remain
closed until the cell is repolarized
back to RMP.

Relative refractory period
• Begins at the end of absolute
refractory period & overlaps
primarily with the period of
hyperpolarization.
• Action potential can be elicited
by stronger than normal
stimulus.
• Cause: Voltage Gated K+
channels are open, so more
inward current is needed to bring
the membrane to threshold for
next action potential

Importance of refractory period
•Responsible for setting up limit on the frequency of
Action Potentials so prevents fatigue
•promotes one way propagation of action potential
because the membrane just behind the ongoing
action potential is refractory due to the inactivation
of the sodium channels

During the activation of nerve cell membrane
a)Na flows outwards
b)K flows inwards
c) Na flows inwards
d)K flows outwards

Depolarization is due to
a)Rapid influx of Na ions
b)Rapid efflux of Na ions
c) Rapid influx of K ions
d)Rapid efflux of K ions

Hyperpolarization is due to increased
conductance of
a)K
b)Na
c) Cl
d)Ca

Which of the following is involved in
maintaining the RMP
a)Outward K current
b)Outward Na current
c) Inward Na current
d)Na K pump

Sudden decrease in serum Ca is associated
with
a) Decreased excitability of muscle and nerve
b) Increased excitability of muscle & nerve
c) Increased phosphate levels
d) Increased release of thyroxine hormone

• The skeletal muscle fibers are
innervated by large myelinated nerve
fibers that originate from large motor
neurons in the anterior horn of spinal
cord
• Each nerve ending makes a junction
called neuromuscular junction with the
muscle fiber near its mid point
• AP initiated in the muscle fiber by the
nerve signal travels in both the direction
towards the muscle fiber length
• There is one such junction per muscle
fiber
Neuromuscular junction

Physiological anatomy of neuromuscular
junction (motor end plate)
• Axons of these motor neurons travel in nerves to
muscle cells
• Axons of motor neurons branch profusely as they
enter muscles called axon terminal
• Each axon terminal forms a neuromuscular
junction with a single muscle fiber
• The motor end plate of a muscle, which is a
specific part of the sarcolemma that contains
receptors and helps form the neuromuscular
junction
• Synaptic gutter or trough: the invaginated
membrane of muscle cell
• Synaptic cleft or synaptic space: the space b/w
axon terminal and fiber membrane
• Subneural clefts: at the bottom of gutter are
numerous folds of cell membrane to increase the
surface area at which neurotransmitter acts

Axon terminal
• Numerous mitochondria which provide
energy for synthesis of neurotransmitter
which excite the muscle membrane
• Secretory vesicles store neurotransmitter
• Acetylcholine binds with receptors on
postsynaptic (motor end-plate) membrane
of muscle cell – activation of Na channel –
depolarization = End plate potential (graded
potential)
• when reaches a threshold action potential is
fired resulting in muscle contraction.

Synthesis & destruction of acetylcholine

Summary Of Sequence Of Events At Neuromuscular Junction )
Acetylcholine bound
to receptor site opens
ligand-gated Na+
channel
Acetylcholine bound
to receptor site opens
ligand-gated Na+
channel
Ca2+Ca2+
Voltage-gated
Ca2+ channel
Voltage-gated
Ca2+ channel
Synaptic
vesicle
Synaptic
vesicle
Postsynaptic
membrane
Postsynaptic
membrane
AcetylcholineAcetylcholine
4
Synaptic cleftSynaptic cleft
Action potentialAction potential
Presynaptic
terminal
Presynaptic
terminal
Na+Na+
1
2
3
1
2
3
1
2
3
11
2
3
4

Motor Unit: The Nerve-Muscle Functional Unit
• A motor unit is a motor neuron and all
the muscle fibers it supplies
• The number of muscle fibers per
motor unit can vary from a few (4-6)
to hundreds (1200-1500)
• Muscles that control fine movements
(fingers, eyes) have small motor units
• Large weight-bearing muscles
(thighs, hips) have large motor
units
• Stronger and stronger
contractions of a muscle require
more and more motor units being
stimulated (recruited)

61
Agents &diseases that alter
the function of
Neuromuscular junction

Drugs that stimulate NMJ
• Black widow spider venom: the venom of black widow spider exerts
its effect by triggering explosive release of Ach from the storage
vesicles, not only at Neuromuscular junction but all cholinergic sites.
All cholinergic sites undergoes prolong depolarization so spasm of
muscles.
• The most harmful result is respiratory failure due to spasm of
respiratory muscles.

Stimulate NMJ by inactivating
acetylcholinesterase
• Drugs such as neostigmine and physostigmine inactivate the acetyl
cholinesterase reversibly in the synapse so that it no longer
hydrolyses acetylcholine so it accumulates leading to muscle spasm
and can cause death due to respiratory failure.

Organophosphate compounds
• Toxic agents are used in some pesticides and military nerve gases
• Irreversibly inhibiting acetylcholinesterase
• Prevents the inactivation of released ACh.
• Spasm of diaphragm
• Respiratory failure

Drugs that block the transmission at NMJ
• Curare : curare competitively binds to Acetylcholine receptor sites
on motor end plate ,so Acetylcholine cannot combine with these sites
to open ion channels and muscles paralysis ensues .
• In severe poisoning person dies of respiratory failure

Botulinum toxin:
Botulinum toxin exerts its lethal effect by blocking the
release of Acetylcholine from the terminal button in
response to a motor neuron action potential .
• Clostridium botulinum poisoning most frequently result
from improperly canned food contaminated with
clostridia bacteria
• Death is due to respiratory failure caused by inability to
contract diaphragm .
66

Therapeutic use of Botox
• Botulinum toxin (Botox) is used by the
cosmetic surgeons to smoothen the
age related wrinkles.
• Wrinkles are formed by facial muscles
that have become over activated or
permanently contracted as a result of
years of performing certain repetitive
facial expressions
• So by relaxing these muscles it
temporarily smoothes out these age
related wrinkles.

Disease of NMJ Myasthenia gravis
• A disease involving N.M junction is characterized by
the extreme muscular weakness
(myasthenia=muscular & gravis=severe)
• It is an auto immune condition (auto immune
means immunity against self) in which the body
erroneously produces antibodies against its own
motor end plate acetylcholine receptors.
• Thus not all Acetylcholine molecules can find
functioning receptors site with which to bind.
• As a results ,Acetyl cholinesterase destroys much of
Acetylcholine before it ever has a chance to interact
with receptor site & contribute to End plate
potential.
• It is treated with long acting acetylcholinesterase
inhibitor pyridostigmine or neostigmine. Which
maintains the Ach levels at NMJ at high levels thus
prolonging the time available for Ach to activate its
receptors. 68

Regarding acetylcholine at motor endplate
the following is true
a) Synthesized in post synaptic membrane
b) Stored in vesicles in presynaptic membrane
c) Enzyme for its synthesis is cholinesterase
d) Enzyme for its hydrolysis is choline acetylase

• Muscles are responsible for all types of body
movements – they contract or shorten and are the
machine of the body
Muscular System

1. Excitability
 the ability to receive and respond to stimuli for e.g. Can respond to chemical
neurotransmitters.
2. Contractility
 Contracts when it is excited
3. Extensibility
 The ability of muscles to be stretched
4. Elasticity
 The ability of muscle to resume a resting length after it has been stretched.
Functional Characteristics of muscles

1. Depending upon striations:
 Striated: e.g. cardiac muscle and skeletal muscle
 Non – striated: smooth muscle
2. Depending upon the control:
 Voluntary: Skeletal muscles
 Involuntary: Cardiac and smooth muscles
3. Depending upon situation:
 Cardiac: in heart
 Skeletal: attached to bones
 Smooth or visceral: present in viscera
Classification of muscles

Skeletal Muscle Microscopic Structure
• Composed of muscle cells (fibers),
• Fibers are long, cylindrical, and multinucleated
and abundant mitochondria
• Striated appearance. Nuclei are peripherally
located
• Cell membrane = sarcolemma. Cytoplasm =
sarcoplasm. SER = sarcoplasmic reticulum
Each muscle fiber has several hundred to
several thousand myofibrils. (80% of cell
volume)
 Myofibrils are aligned to give distinct bands
 I band = light band & A band = dark band

Myofibril
• Each myofibril is composed of
myosin filaments and actin
filaments which are large
polymerized protein molecules
made up of polymerization of
proteins myosin and actin
molecules respectively that are
responsible for the actual
muscle contraction.

A band- anisotropic to polarized light
• With an electron microscope , a
myofibril displays alternating dark bands
(A band) and light band (I band) .
• A bands: a dark band; full length of thick
filament & the portions of thin
filaments that overlaps on both ends of
the thick filaments
• H zone - thick but NO thin filaments
• M line –system of supporting
proteins which hold the thick
filaments together vertically within
each stack (protein to which myosins
attach)

I band ( Isotropic to polarized light)
• Having like properties in all directions
(singly refractive)
• I bands: a light band; it is made up of
the remaining part of actin filament on
the 2 adjoining sides of sarcomeres
• Only thin but NO thick filaments
• In the middle of I band is a Z line
• Z disk: filamentous network of protein.
Serves as attachment for actin filaments of
the two adjoining sarcomeres
• So I band extends from A band of one
sarcomere to A band of the next
sarcomere

• The distance between two successive Z lines is called
sarcomere which is the functional unit of the skeletal muscle.
• Each relaxed sarcomere is 2.5 μm in width and consists of one
whole A band and half of each of the two I bands located on
either side.
sarcomere

Length and tension relationship
• Length of fiber at onset of
contraction is a very
important factor influencing
extent to which tension can
be developed in a muscle
• Muscles operate with greatest
active force when close to
resting length 2.5μm. When
stretched or shortened
beyond this, the maximum
active force generated
decreases

Titin
• Titin filaments: single strand of giant,
elastic protein called titin extend in
both direction from the M line along
the length of the thick filament to the
Z lines it is the largest protein in the
body with 30,000 amino acids
• It stabilizes the position of myosin
filament and increases muscle
elasticity

Molecular characteristics of the contractile
filaments
• Myosin forms the thick or myosin filament
• Each thick filament is formed by the polymerization of 200 or more
myosin molecules

A single myosin molecule
• It is a protein containing 2 identical
subunits , each shaped like a golf club.
The tails or 2 heavy chains of myosin
molecules wound together to form a rod
portion lying parallel to the myosin
filament and two heads projecting out at
one end.

• The tails of the myosin molecules
bundled together to form the
body of myosin filament while
heads of the molecules hang
outward to the sides of the body
• Mirror image of each other
• Also part of the body of each
myosin molecule hangs to the side
along with the head thus providing
an arm

Binding sites
1. Actin binding site : Can bind to
active sites on the actin
molecules
2. ATP binding site which has
ATPase activity that breaks down
ATP, releasing energy.

Ultrastructure of actin filament
• The backbone of thin filaments are
chiefly composed of the actin
• Each actin molecule is a helical
polymer of globular or spherical
subunits called G actin which are
linked to create the F actin filaments
• It contains the active sites to which
myosin cross bridge attach during
contraction
• Tropomyosin and troponin are
regulatory subunits bound to actin
Thin filaments = actin filaments
Composed of 3 proteins

Troponin Complex
• TnI – bound to the actin fiber and is
inhibitory, by blocking the binding site
• TnT – bound to the tropomyosin fiber holding
it in place
• TnC – will bind to Ca++
ions
• When no Ca bound to troponin , it stabilizes
tropomyosin in its blocking position over
active sites of actin filament.
• But when Ca binds to troponin, the shape of
this protein is changed in such a way that
tropomyosin slips away from its blocking
position so now actin and myosin filament
can bind with each other and result in muscle
contraction.

Excitation – Contraction Coupling
• Excitation-contraction (EC) coupling is the
physiological process of converting an electrical
stimulus into mechanical response.
• Electrical stimulus is an action potential
• Mechanical response is contraction

Transverse tubules
• These are invaginations of
sarcolemmal membrane deep
into the muscle fiber
• They carry the action potential
from the muscle membrane
deep into the muscle fiber
• T tubule make contact with the
terminal cisternae of the
sarcoplasmic reticulum and
contain voltage sensitive
dihydropyridine receptor

Sarcoplasmic Reticulum (SR)
• SR is an elaborate, smooth
endoplasmic reticulum surrounding
each myofibril. It consists of 2 parts
• terminal cisternae on either side of
the T-tubules
• Longitudinal tubules
• A single T-tubule and the 2
terminal cisternae form a triad
• Ca is accumulated in the SR by Ca
ATPase pump in its membrane
when contraction is over
• Within the SR Ca is bound to
calsequestrin, a Ca binding protein

SR cont..
• SR has Ca released channel called
ryanodine receptor & when
stimulated, calcium released into
sarcoplasm
• Depolarization of the T tubules causes
a conformational change in the
dihydropyridine receptor.
• This conformation opens the
ryanodine receptors (Ca release
channels) on the nearby SR and Ca is
released in the sarcoplasm and cause
muscle contraction

Cross bridge cycling or walk along
theory

• Activation by nerve causes myosin
heads (cross bridges) to attach to
binding sites on the thin filament
• Myosin heads then bind to the next
site of the thin filament
• This continued action causes a sliding
of the actin filament along the myosin
filament.
• The result is that the muscle is
shortened (contracted)
Cross bridge cycling

RIGOR MORTIS
• Rigor mortis is the stiffening of
muscles once a person dies.
• ATP is needed for myosin head to
release actin; in absence of ATP, the
muscle is unable to detach.
• With the lack of oxygen and
circulation, ATP production quickly
stops.
• It takes ~ 48-60 hours for muscle
proteins to breakdown & for the
muscle to “relax”.

Actin filaments slide over myosin to shorten sarcomeres
Actin and myosin do not change length
Shortening sarcomeres responsible for skeletal muscle contraction
During relaxation, sarcomeres lengthen

Mechanism of muscle contraction
• The above micrographs show that the sarcomere gets
shorter when the muscle contracts
• The light (I) bands become shorter
• The dark bands (A) bands stay the same length
• The H zone shortens
Relaxed
muscle
Contracted
muscle
relaxed sarcomere
contracted sarcomere

Relaxation of the skeletal muscle
•When no stimulus Ca ions are pumped back
into the SR since non availability of Ca so no
muscle contraction and muscle relaxed

Summary – Muscle Contraction &
RELAXATION
1.Acetylcholine is released
at neuromuscular junction
2.AP is propagated along membrane
& down T-tubule
3.Ca released from SR via a voltage
gated Ca channel
4.Ca binds to Troponin-C -
conformation changes favor
tropomyosin opening actin myosin
binding sites.
5.myosin cross-bridges attach-detach
from actins... pulls actin filament
toward M-line.
6.Ca is removed by Ca-pump (uptake
by SR)
7.tropomyosin blocks actin sites and
muscle relaxes.

Muscle Twitch
A muscle twitch is the response of
a muscle to a single, brief threshold
stimulus or response to a single
action potential.
It is too short or too weak to be
useful
E. g. blinking of the eye
There are three phases of muscle
twitch
Latent period
Period of contraction
Period of relaxation

Phases of a Muscle Twitch
Latent period – first few msec after
stimulus; excitation Contraction
coupling taking place
Period of contraction – muscle
tension develops; muscle shortens
Period of relaxation – Ca2+
reabsorbed; muscle tension goes to
zero
The entire contractile response to
a single AP last for about 100msec

Motor unit
• Motor unit - all muscle cells
innervated by the same
motoneuron – they will contract at
the same time
• Motor units vary in size - mostly
mixture of motor units of different
sizes
large motor units >100 cells
(typically slow postural muscles)
small motor units about 10
cells (precise control fast acting
muscles – those moving the eye)

Summation
Adding together individual twitch contractions to increase the
intensity of overall muscle contraction.
Summation occur in 2 ways:
1.By increasing the number of motor units contracting simultaneously
(multiple fiber summation or motor unit recruitment)
2.By increasing the frequency of contraction which can lead to
tetanization. (frequency summation)

Motor Unit Recruitment
For stronger & stronger contractions, more &more
motor units are recruited or stimulated to contract

Stimulus Intensity and Muscle Tension
Figure 9.16

Size principle
A concept known as the size principle,
allows for a gradation of muscle force
during weak contraction to occur in small
steps, which then become progressively
larger when greater amounts of force are
required.
Cause of size principle:
Smaller motor units are driven by small
motor nerve fibers and the small motor
units are more excitable than the larger
ones so they naturally are excited first.

Frequency summation or tetanization
• Tetanization:
• Occurs if muscle fiber is
stimulated so rapidly that
it does not have a chance
to relax between stimuli
• Contraction is usually
three to four times
stronger than a single
twitch
• Results from sustained
elevation of cytosolic
calcium

Tetany
• Medical sign, involuntary
contraction of muscles, due to
increased AP frequency
• Low calcium  neurons
depolarize easily
Tetanus
• Medical condition caused by
prolonged contraction of
skeletal muscles
• Wound – spores of bacteria
Clostridium Tetani enter –
germinate – produce
neurotoxin
• Cause muscle spasm

• Isometric (same length)
• Muscle does not shorten
• Does not require much sliding of
filaments, but force is developed
• No external work done
as W = F X D
• Eg. Sitting, standing, maintaining
posture, pushing against the wall
• Isotonic (same tension)
• Muscle shortens
• Sliding of filaments occurs, load
is moved
• External work is done
• Eg. Walking, moving any part of
body

Energetic of muscle contraction
•When the muscle contract against the load it
perform the work and the energy required to
perform the work is derived from the chemical
reaction in the muscle cells during contraction
Most of the energy is required for:
1. Walk along theory
2. Ca pump
3. Na K pump

Energy Sources for Contraction
Muscle contraction depends on the energy supplied by the
ATP
Since ATP is the only source of energy that directly be
used for contractile activity to continue, so ATP must be
constantly supplied
Only limited stores of ATP are immediately available in
muscle tissue which produces muscle contraction for 1-2
seconds
 3 pathways supply additional ATP as needed during
muscle contraction

Skeletal Muscle Energy Metabolism
3 ways to form ATP in a Muscle fiber

Importance of glycolysis
• Glycolytic reaction can occur even in
the absence of oxygen so muscle
contraction can be sustained up to a
minute when oxygen delivery from
blood is not available
• Rate of formation of ATP by glycolysis
is 2.5 times faster as compared to
oxidative phosphorylation

Consequences of glycolysis
Large amount of nutrient fuel is used giving less
amount of energy so glycolysis rapidly depletes the
storage pool of glycogen
Lactic acid production may cause pain and stiffness
in the muscle
So both factors play a role in the onset of muscle
fatigue

Oxidative phosphorylation
 More than 95% of all energy used by
muscles for sustained long term
contraction is derived from this source
 The food stuffs consumed during this
process are :
 Carbohydrates
 Fats
 Proteins
For long term maximal contraction
(period of hours) greatest energy
production from fats

Oxygen supply and cellular respiration
• The early phase of cellular respiration yields few molecules
of ATP, so muscle has a high requirement for oxygen, which
enables the complete breakdown of glucose in the
mitochondria
• Hemoglobin in RBCs carries oxygen to muscles
• The pigment myoglobin stores oxygen in muscle tissue

Oxygen Debt
• During rest or moderate activity, there is enough oxygen to
support aerobic respiration.
• Oxygen deficiency may develop during strenuous exercise, and
lactic acid accumulates as an end product of anaerobic
respiration.
• Lactic acid diffuses out of muscle cells and is carried in the bloodstream
to the liver.
• Oxygen debt refers to the amount of oxygen that liver cells
require to convert the accumulated lactic acid into glucose, plus
the amount that muscle cells need to resynthesize ATP and
creatine phosphate to their original concentrations.
• Repaying oxygen debt may take several hours.

Major Types of Muscle Fibers
• Every muscle of the body is composed of a mixture of fast and
slow fibers and other fibers gradated b/w these two extremes
• Two major types
• Slow-oxidative (type I) fibers (Slowly acting muscles but with
prolonged contraction are composed of mainly slow fibers
(soleus muscle)
• Fast-glycolytic (type II) fibers (Rapidly acting muscles are
composed of fast fibers mainly)

Red Muscle - Type I
Slow oxidative type
• Rich in myoglobin  red in color
• Numerous mitochondria
• Depend on cellular respiration for
ATP production
• Resistant to fatigue
• Slow contraction (Slow-twitch fibers)
• Dominant in muscles used for
posture
White Muscle - Type II
Fast glycolytic
• Low in myoglobin whitish in color
• Few mitochondria
• Rich in glycogen and depend on
glycolysis for ATP production
• Fatigue easily
• Fast contraction (Fast-twitch fibers)
• Dominant in muscles used for rapid
movement

Fatigue
• Decreased capacity to work and reduced
efficiency of performance
• Types:
• Psychological
• Depends on emotional state of individual
• Muscular
• Results from ATP depletion
• Synaptic or fatigue of NMJ
• Occurs in neuromuscular junction due to lack of
acetylcholine. In intact organism it is unlikely to be
the site of fatigue

Causes of Muscle Fatigue
Lack of oxygen causes ATP deficit
Lactic acid builds up from anaerobic glycolysis
A local increase in ADP and inorganic phosphate from
ATP breakdown which will interfere with cross bridge
cycling
Accumulation of ECF K+ when Na K pump cannot
transport K back into muscle so decrease in
membrane potential so decrease excitability
Depletion of glycogen energy reserves

Smooth muscle or plain muscle
Smooth muscle fibers - a fusiform
shape –
- a spindle-like shape with single
nucleus (wide in the middle and tapers
at both ends)
- small diameter and length of fibers
• Group of muscle cells are arranged in
sheets
• No striations
• Filaments do not form myofibrils
• Not arranged in sarcomere & banding
pattern as found in skeletal muscle

Smooth Muscle
• Cell has three types of filaments
arranged diagonally
• Have dense bodies containing same
protein found in Z lines
• Thick myosin filaments
• Longer than those in skeletal muscle
• Thin actin filaments
• Contain tropomyosin but lack troponin
• Filaments of intermediate size
• Do not directly participate in contraction
• Form part of cytoskeletal framework
that supports cell shape

Types of smooth muscles
• Single unit smooth muscle (unitary
smooth muscle or visceral smooth
muscle)
• Mass of hundreds or thousands of
smooth muscle fibers that contract as
a single unit
• Arranged in sheets or bundles
• Fibers become excited and contract as
single unit
• Cells electrically linked by gap
junctions
• Can also be described as a functional
syncytium

Single-unit Smooth Muscle
• it is myogenic (via ionic channel dynamics or special pacemakers cells
- interstitial cells of Cajal e.g. in the gastrointestinal tract)
• Self-excitable (does not require nervous stimulation for contraction)
• So don’t have constant RMP
• Their RMP fluctuates without any influence by factors external to the
cell
• Well suited for forming walls of distensible, hollow organs e.g. gut,
bile ducts, ureters , uterus , and blood vessels

Multiunit Smooth Muscle
• Its properties are partway b/w skeletal
muscle & single unit smooth muscle
• Neurogenic (innervated by a single nerve
ending like skeletal muscle)
• Consists of multiple discrete units that
function independently of one another
• Units must be separately stimulated by
nerves to contract
• Found
• In muscle of eye that adjusts lens for
near or far vision(ciliary muscle)
• In iris of eye
• At base of hair follicles (pilo erector
muscle)

Contractile mechanism in smooth muscle
• Similarities to skeletal muscle:
Actin and myosin interact with each other
Contraction activated by Ca ions
ATP is degraded to ADP
Differences:
Physical organization
In excitation contraction coupling
Control of contraction by Ca ions
Duration of contraction
Amount of energy required

Smooth muscle
• No T-tubules, SR is poorly developed
• So Calcium comes from 2 sources
Mainly from ECF
Some from sparse SR stores
• Excitation-contraction coupling-
• Calcium binds to calmodulin
• Causes phosphorylation of myosin light chain kinase

No T tubules
• Because the diameter of smooth muscle
cells are so small most of the Ca entering
from ECF can influence cross bridge
activity even in the central region of the
cell without requiring an elaborate T –
Tubule - Sarcoplasmic reticulum
mechanism
• Plasma membranes have pouch like
infoldings called caveoli . Ca2+
is
sequestered in the extracellular space
near the caveoli, allowing rapid influx
when channels are opened

Calcium Activation of Myosin Cross Bridge in Smooth Muscle

Comparison of Role of
Calcium In Bringing About
Contraction in Smooth
Muscle and Skeletal
Muscle

Relaxation of smooth muscle
•It is brought about by removal of Ca
•They are actively pumped out across the plasma
membrane and also back in Sarcoplasmic
reticulum
•When no Ca myosin is dephosphorylated and
no longer can interact with actin relaxing the
muscle

Comparison of smooth and skeletal muscle
contraction
•Most skeletal muscle contract and relax
rapidly and most smooth muscle
contraction is prolonged tonic contraction
lasting for hours or days .
•What causes this differences?

1) Slow cycling of myosin cross bridge cycling
•The attachment of cross bridges to actin then
release from actin and reattachment for the next
cycle is much slower in smooth muscle than
skeletal muscle
•It is due to less ATPase activity of myosin cross
bridge than skeletal muscle

2) Energy required to sustain muscle
contraction
•Very less energy is required to sustain the same
tension of contraction in smooth muscle as in
skeletal muscle. It is due to slow attachment and
detachment cycling of cross bridges and
because one molecule of ATP is required for
each cycle regardless of its duration

3) Slowness of onset of contraction &
relaxation
•The duration of contraction is much prolong in
smooth muscle as compared to skeletal muscle
•It is 30 times as long as skeletal muscle
•The slow onset and prolong contraction is due to
slow cycling of myosin cross bridge cycle

4) Force of muscle contraction
•The maximum force of contraction of
smooth muscle is greater than that of
skeletal muscle due to prolong attachment
of myosin cross bridges to the actin
filaments

Latch phenomenon for prolonged holding of smooth muscle
contractions
•“Latch Mechanism - prolonged holding in
smooth muscle
a. After contraction is initiated, less stimulus and
energy are needed to maintain the contraction
(Energy conservation)
b. Can maintain prolonged tonic contractions for
hours with little energy and little excitatory signal
from nerves or hormones

SMOOTH MUSCLE
STIMULATION
• Smooth muscle responds to stimulation from a
number of different physiological systems.
1. Nerves
2. Hormones
3. Mechanical manipulation (stretch)
4. Self stimulation (Automaticity)

A comparison of the properties
of skeletal, cardiac, and visceral muscle
Property
Skeletal
Muscle
Cardiac
Muscle
Smooth
Muscle
Striations? Yes Yes No
Relative Speed
of Contraction
Fast Intermediate Slow
Voluntary Control? Yes No No
Membrane
Refractory Period
Short Long
Nuclei per Cell Many Single Single
Control of
Contraction
Nerves
Beats
spontaneously
but modulated by
nerves
Nerves
Hormones
Stretch
Cells Connected by
Intercalated Discs or
Gap Junctions?
No Yes Yes

Nerve and muscle physiology

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