PHYSIOLOGY OF MUSCLES

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 The membrane potential, RMP, ion channels

Membrane potential
 A separation of opposite charges across the plasma membrane is
called a membrane potential
 the plasma membranes of all living cells have a membrane
potential, or are polarized electrically

 Membrane potential results from differences in the concentration ions

across cell membrane and permeability of the membrane for key ions
 all cells have membrane potential
 The cells of excitable tissues—namely, nerve cells and muscle
Cells—have the ability to produce rapid, transient changes in
their membrane potential (action potential) when excited

Dilnessa F. 2
 The membrane … cont’d

 The constant membrane potential present in the cells of non-

excitable tissues and those of excitable tissues when they are at
rest—that is, when they are not producing electrical signals, the
resting membrane potential

• At rest, there are electropositivity out and electronegativity

inside in cell membrane of the neuron & muscle tissue.

Dilnessa F. 3
 The membrane … cont’d

 the unequal distribution of a few key ions between the ICF and the
ECF and their selective movement through the plasma membrane are
responsible for the electrical properties of the membrane
 Na+ is more concentrated in the ECF and K+ is more concentrated in
the ICF
 these concentration differences are maintained by the Na+–K+ pump
at the expense of energy
 because the plasma membrane is virtually impermeable to negatively
charged intracellular proteins, these large, negatively charged proteins
are found only inside the cell
 at resting potential in a nerve cell, the membrane is typically about 25
to 30 times more permeable to K+ than to Na+

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• What are the causes of the RMP?
 An outward diffusion of K+ through K+ leak channels. The ECF
is very high in Na+ while the ICF is very high in K+. As a result, K+
is constantly leaking out of the cell.

 The Na+/K+ pump is constantly pumping 3 Na+ ions out and 2 K+

ions in for every ATP used. Thus more positive charge is leaving
than entering.
 There are protein anions (i.e., negatively charged proteins) within
the ICF that cannot travel through the PM.

• What this adds up to is the fact that the inside of the cell is
negative with respect to the outside. The interior has less
positive charge than the exterior.

Dilnessa F. 5
The membrane … cont’d

Dilnessa F. 6
 Basic Electrophysiological Terms
Polarization
- a state in which membrane is polarized at rest, negative inside
and positive outside.
Depolarization:
- the membrane potential becomes less negative than the resting
potential (-70 mV).(the reverse of polarization due to the rapid
opening of Na+ channel )
Repolarization:
- when the membrane recover (returns) to the resting potential
after depolarization.(due to the slower opening of K+channels
and the closing of Na+ channels )
Hyperpolarization:
- membrane potential become more negative than the resting
potential (-70 mV).(due to theDilnessa
outF. flow of K+ may be so great)7
• Excitability: the ability to respond to a stimulus and convert it
into an action potential.
• Excitable cells: cells that generate action potential during
excitation. nerve cells and muscle cells

• Stimulus : any change in the environment (internal or external

environmental condition of the cell).

• Threshold stimulus: any stimulus strong enough to initiate an

action potential (nerve impulse).

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 Role of Ion Channels
 Ion channels are transmembrane proteins whose function is the
transport of ions across the plasma membrane to regulate cell
membrane potential and play an essential role in neural
communication, nerve conduction, and muscle contraction.
 Movement is through ion channels.
I. Leak channels: non-gated, always open
II. Gated channels: opened and closed in response to specific
triggering events. Of three types:
1. Voltage-gated channels:
- respond to changes in membrane potential
2. Chemically gated channels (ligand gated):
- respond to binding of a specific chemical messenger
3. Mechanically gated channels:
- respond to stretching or other mechanical deformation.
Dilnessa F. 9
 Action potential (nerve impulse)

 Action potential is a brief, rapid changes in membrane potential

during which the potential actually reverses so that the inside of the
excitable cell transiently becomes more positive than the outside
 An action potential is a rapid rise and subsequent fall in voltage or
membrane potential across a cellular membrane with a characteristic
pattern.
 ... Examples of cells that signal via action potentials are neurons and
muscle cells.
 Stimulus starts the rapid change in voltage or action potential

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 Action Potentials
• If membrane potential reaches threshold, Na+ channels open and
Na+ influx , depolarizing the cell and causing the membrane
potential to increase.
- This is the rising phase of an AP
• Eventually, the Na+ channel will have inactivated and the K+
channels will be open. Now, K+ effluxes and repolarization
occurs.
- This is the falling phase.
• K+ channels are slow to open and slow to close. This causes the VM
is became Hyperpolarization.

• An action potential is a rapid rise and subsequent fall in voltage or

membrane potential across a cellular membrane with a
characteristic pattern.

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Action Potentials

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Dilnessa F. 13
Action potential cont’d

Action potential occurs only if the change

in membrane potential at the axon
hillock is above threshold.
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Physiology of Muscle

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 Muscle Tissue Types
• Skeletal
– Attached to bones
– Nuclei multiple and peripherally located
– During development, 100 or more myoblasts, a type of
mesodermal cell, fuse to form a skeletal muscle fiber.
– Striated, Voluntary and involuntary (reflexes)
• Smooth
– Walls of hollow organs, blood vessels, eye, glands, skin
– Single nucleus centrally located
– Not striated, involuntary, gap junctions in visceral smooth
• Cardiac- In the heart only.
– Single nucleus centrally located
– Striations, involuntary, intercalated
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Dilnessa F. 17
 Cardiac Muscle
• Branching cells
• One/two nuclei per cell
• Striated
• Involuntary
• Medium speed contractions

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 Smooth Muscle

• Fusiform cells
• One nucleus per cell
• Nonstriated
• Involuntary
contractions

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 Muscle Functions
1. Produces Movement
– Movement of body parts
– Movement of blood throughout the body
– Movement of lymph through the lymphatic vessels
– Movement of food through the GI tract
– Movement of bile out of the gallbladder and into the
digestive tract
– Movement of urine through the urinary tract
– Movement of semen through the male and female
reproductive tracts
– Movement of a newborn through the birth canal

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 Muscle Functions
2. Maintenance of posture
– Muscle contraction is constantly
allowing us to remain upright.
– The muscles of your neck are
keeping your head up right now.
– As you stand, your leg muscles keep
you on two feet.
3. Thermogenesis
– Generation of heat. Occurs via
shivering – an involuntary
contraction of skeletal muscle.

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 Muscle Functions
4. Stabilization of joints
– Muscles keep the tendons
that cross the joint nice
and firm This does a
wonderful job of
maintaining the integrity
of the joint.

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 Characteristics of Muscle Tissue
1. Excitability
– The ability to receive and respond to a stimulus
• In smooth muscle, the stimulus could be a
neurotransmitter, a hormone, stretch, Pco2, or
Po2.
• In cardiac muscle, the stimulus could be a
neurotransmitter, a hormone.
– The response is the generation of an electrical
impulse that travels along the plasma membrane of
the muscle cell.
• In skeletal muscle, the stimulus is a
neurotransmitter released by a neuron.

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 Characteristics of Muscle Tissue

2. Contractility
– The ability to shorten forcibly when adequately
stimulated.
– This is the defining property of muscle tissue.
3. Extensibility
– The ability to be stretched
4. Elasticity
– The ability to recoil and resume original length
after being stretched or contracted.

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 skeletal muscles structure
 the entire muscle tissue is covered by outermost layer connective
tissue the epimysium
 in the muscle tissue groups of 10 -100 or more muscle fibers form
bundles called fascicles which are covered by a layer connective
tissue the perimysium
 the interior of each fascicle there individual muscle fibers that are
covered by a layer connective tissue the endomysium

 the epimysium, perimysium, and endomysium all are continuous

with the connective tissue that attaches skeletal muscle to other
structures, such as bone or another muscle

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Skeletal Muscle Structure

Dilnessa F. 26
 Skeletal Muscle structures

 Each skeletal muscle cell is known

as a skeletal muscle fiber because
 they are so long.
– Their diameter can be up to 100µm
– and their length can be as long as 30cm.

Dilnessa F. 27
Muscle
fiber PM is
known as
sarcolemm
a
Muscle
fiber
cytoplasm
is known
as
sarcoplasm

Sarcolemma has invaginations that penetrate through the cell called

transverse tubules or T tubules.

Sarcoplasm has lots of mitochondria (why?), lots of glycogen granules

(to provide glucose for energy needs) as well as myofibrils and
sarcoplasmic reticuli. Dilnessa F. 28
 Sarcoplasmic Reticulum

• Muscle cell version of the smooth

endoplasmic reticulum.

• Functions as a calcium storage

depot in muscle cells.

• Loose network of this membrane

bound organelle surrounds all the
myofibrils in a muscle fiber.

• We will see why this is so

important soon.

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 Myofibrils
• Each muscle fiber contains rodlike structures called myofibrils that
extend the length of the cell. They are basically long bundles of
protein structures called myofilaments and their actions give
muscle the ability to contract.
• The myofilaments are classified as thick filaments and thin
filaments.

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 Muscle Proteins
• Contractile Proteins (actin and myosin)
• Regulatory Proteins (i.e. tropomyosin and troponin)

• Troponin- these are actually complexes of three loosely

bound protein subunits; (troponin I) has a strong affinity
for actin, (troponin T) for tropomyosin, and a third
(troponin C) for calcium ions

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 Myofilaments

• 2 types of myofilaments (thick & thin) make up myofibrils.

• Thick myofilaments are made up of the protein myosin

A single myosin protein

resembles 2 golf clubs
whose shafts have been
twisted about one another

About 300 of these

myosin molecules are
joined together to form a
single thick filament
Dilnessa F. 32
 Each thin filament is made up of 3 different types of
protein: actin, tropomyosin, and troponin.
– Each thin filament consists of a long helical double strand.
This strand is a polymer that resembles a string of beads. Each
“bead” is the globular protein actin. On each actin subunit,
there is a myosin binding site.
– Loosely wrapped around the actin helix and covering the
myosin binding site is the filamentous protein, tropomyosin.
– Bound to both the actin and the tropomyosin is a trio of
proteins collectively known as troponin.

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Note the relationship between the thin and thick filaments

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 Myofibrils
• Each myofibril is made up 1000’s of repeating individual units
known as sarcomeres (pictured below)
• Each sarcomere is an ordered arrangement of thick and thin
filaments. Notice that it has: regions of thin filaments by
themselves (pinkish fibers)
– a region of thick filaments by themselves (purple fibers)
– regions of thick filaments and thin filaments overlapping.
• myofibril consists of a regular arrangement of highly organized
cytoskeletal elements—the thick and the thin filaments

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• Each muscle T-Tubules and the SR
fiber has many
T-tubules
– Typically
each
myofibril has
a branch of a
T-tubule
encircling it
at each A-I
junction

Each T-tubule will be flanked by a

terminal cisterna. This forms a so-called
triad consisting of 2 terminal cisternae
and one T-tubule branch.
Dilnessa F. 36
 Muscle contraction

• All the sarcomeres in a fiber will contract together. This

contracts the fiber itself.

• The number of fibers contracting will determine the force of

the contraction of the whole muscle.

• We can actually divide the whole process of muscle

contraction into 4 steps:
– Excitation
– Excitation-contraction coupling
– Contraction
– Relaxation
Dilnessa F. 37
 Excitation
• The PM has integral proteins that act as gated ion channels.
These are channels that are normally closed, but in response to
a certain signal, they will open and allow specific ions to pass
through them.
• Ion channels may be:
– Ligand-gated  the binding of an extracellular molecule
(e.g., hormone, neurotransmitter) causes these channels to
open.
– Voltage-gated  Vm causes these channels to open.
– Mechanically-gated  stretch or mechanical pressure
opens these channels.
• When a channel is open, its specific ion(s) will enter or exit
depending on their electrochemical gradient.

Dilnessa F. 38
 Excitation
• In general each muscle is
served by one nerve – a bundle
of axons carrying signals from
the spinal cord to the muscle.
• W/i the muscle, each axon will
go its own way and eventually
branch into multiple small
extensions called telodendria.
Each telodendrium ends in a
bulbous swelling known as the
synaptic end bulb.

The site of interaction btwn a neuron and any other cell is

known as a synapse. The synapse btwn a neuron and a
muscle is known as the neuromuscular junction.
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 Excitation
The minute space between the synaptic end bulb and the
sarcolemma is known as the synaptic cleft.
There is a depression in the sarcolemma at the synaptic cleft
known as the motor end plate.
The synaptic end
bulb is filled w/
vesicles that
contain the
neurotransmitter,
acetylcholine.
The motor end
plate is chock full
of acetylcholine
receptors.
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 Excitation
1. A nerve signal will arrive at the synaptic end bulb and this will
cause the ACh-containing vesicles to undergo exocytosis.
2. ACh will diffuse across the synaptic cleft and bind to the ACh
receptors. These receptors are actually ligand-gated Na+
channels. The binding of ACh causes them to open.

3. Na+ will rush

into the cell,
making the
local cell
interior more
positive. This
is known as
depolarization.
It is a local
event!
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 Excitation
 Adjacent to the motor end plate, the sarcolemma contains
voltage-gated ion channels.
 In order for these channels to open, the Vm must depolarize from
its resting value of –90mV to approximately –50mV. This is the
threshold.
 Vm must become this positive for the voltage-gated channels to
open.

 The degree of depolarization depends on how much Na+ influx

occurred which in turn depends on how many Na+ channels were
opened by binding ACh.

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 Excitation
• If the Vm fails to depolarize to threshold, nothing will happen.
The Vm will soon return to normal and no muscle contraction
will occur.
• If the Vm does reach threshold, 2 types of voltage-gated ion
channels will open:
– Fast Na+ channels
– Slow K+ channels

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• If Vm reaches threshold, fast Na+ channels open and Na+ rushes in
causing the Vm to depolarize to +30mV.
• The depolarization stops when the Na+ channels become inactivated.
• At this point, slow K+ channels have opened & K+ efflux occurs. This
returns Vm back to its resting level. This is repolarization.
• If we were to graph this change in Vm over time, it would look
somewhat like the animation below.
• This is known as an action potential.

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• An AP can propagate itself across
the surface of the PM.
• The depolarization caused by the
Na+ influx in one particular area of
the sarcolemma causes voltage-
gated channels in the adjacent
membrane to open.

• The resulting ionic influx then

causes voltage-gated channels to
open in the next patch of
membrane and so on and so on.
Thus the AP propagates itself.

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 Excitation-Contraction Coupling
The AP travels along the sarcolemma going in both directions away
from the motor end plate.
Since T-tubules are simply invaginations of the sarcolemma, the AP
will spread down and through them as well. This is really important!

Dilnessa F. 46
 Excitation-Contraction Coupling
• The T-tubular sarcolemma contains voltage sensitive proteins (red
arrow in the picture below) that change their conformation in
response to a significant Vm.
– These are physically linked to calcium channels in the SR
membrane
– Upon Vm, the voltage sensors change their conformation.
This mechanically opens the Ca2+ channels in the SR
membrane.

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 Excitation-Contraction Coupling
The SR Ca2+ channels are only open briefly, but a large Ca2+
gradient exists so a large amount of calcium enters the sarcoplasm.

The Ca2+
interacts w/ the 2
regulatory
proteins of the
sarcomere so that
the 2 contractile
proteins can slide
& the sarcomere
can shorten.

Dilnessa F. 48
 …

• Now that we know what an action potential is, it

should be noted that the exocytosis of the ACh
vesicles is caused by the arrival of an AP at the
synaptic end bulb.
• The AP causes the opening of voltage-gated Ca2+
channels in the synaptic end bulb plasma membrane.
The resulting calcium influx causes the exocytosis of
the vesicles.

Dilnessa F. 49
 Contraction
• Normally, tropomyosin obstructs
the myosin binding site on the
G-actin subunits.
• Calcium binds to the troponin-C
polypeptide of the troponin triad.

• This changes the conformation

of troponin which changes the
conformation of tropomyosin
which exposes the myosin
binding site on actin.

Dilnessa F. 50
 Contraction

• Once actin’s myosin binding site is exposed, myosin will attach to

it.
– At this point myosin has just hydrolyzed ATP into ADP and Pi
– however both molecules are still bound to the myosin.
– The ATP hydrolysis provides the energy for the “cocking” of
the myosin head
• Once myosin is bound to actin, the myosin head will release the
ADP and Pi which will cause it change conformation. This
results in the thin filament sliding along the thick filament.
• Myosin then remains bound to actin until it binds to another ATP.
Myosin then hydrolyzes the new ATP and the cycle can begin
again.
Dilnessa F. 51
• Step 1: ATP hydrolysis

• Step 2: Attachment

Dilnessa F. 52
• Step 3: Power Stroke

• Step 4: Detachment

Dilnessa F. 53
 The Cross Bridge Cycle
Myosin head ADP
(high-energy Pi
configuration)

1 Myosin head attaches to the actin

myofilament, forming a cross bridge.
Thin filament

ADP Thick filament ADP

ATP
hydrolysis Pi

4 As ATP is split into ADP and Pi, the myosin
head is energized (cocked into the high-energy
conformation).
2 Inorganic phosphate (Pi) generated in the previous
contraction cycle is released, initiating
the power (working) stroke. The myosin head
pivots and bends as it pulls on the actin filament,
sliding it toward the M line. Then ADP is released.

ATP
Myosin head
ATP (low-energy
configuration)

3 As new ATP attaches to the myosin head, the link between

Myosin and actin weakens, and the cross bridge detaches.
Dilnessa F. 54
 POWER STROKE
 The myosin heads or cross bridges “walk” along an actin
filament to pull it inward relative to the stationary thick filament.

 A single power stroke pulls the thin filament inward only a small
percentage of the total shortening distance.

 Repeated cycles of cross-bridge binding and bending complete

the shortening.

Dilnessa F. 55
 Relaxation
• Calcium pumps in the SR membrane work
constantly to get the calcium out of the
sarcoplasm and back into the SR.
• They are unable to do this as long as the
muscle is still binding ACh.
• ACh is released by the motor neuron as long
as it keeps being stimulated.

• Note that ACh does not remain bound to the

AChR for very long. It quickly releases and
either binds again or more likely is hydrolyzed
by the enzyme acetylcholinesterase which
exists as part of the sarcolemma and free w/i
the synaptic cleft

Dilnessa F. 56
 Relaxation
• When the muscle ceases being
stimulated, the calcium pumps
“win” and sarcoplasmic
[Ca2+] drops.
– Calcium stops being
available for troponin and
tropomyosin shifts back
into its inhibitory position.
• The muscle then returns back
to its original length via the
elasticity of the connective
tissue elements, plus the
contraction of antagonistic
muscles. Dilnessa F. 57
 Muscle Relaxation Mechanism

1. Acetylcholinesterase present in the NMJ destroys

ACh (preventing continual stimulation)

2. Calcium ions are transported from the

sarcoplasm back into the SR

3. Linkages between myosin and actin are broken

• THEN: The muscle fiber relaxes

Dilnessa F. 58
 Rigor Mortis
• Rigor mortis is a postmortem change resulting in the
stiffening of the body muscles due to chemical changes in
their myofibrils. Rigor mortis helps in estimating the time
since death as well to ascertain if the body had been moved
after death.
• Upon death, muscle cells are unable to prevent calcium entry.
This allows myosin to bind to actin. Since there is no ATP
made postmortem, the myosin cannot unbind and the body
remains in a state of muscular rigidity for almost the next
couple days.

Dilnessa F. 59
 Smooth Muscle
• Involuntary, non-striated muscle tissue
• In Cardiovascular system:
– Smooth muscle in blood vessels regulates blood flow through vital
organs.
– Smooth muscle also helps regulate blood pressure.

• Digestive systems:
– Rings of smooth muscle, called sphincters, regulate movement
along internal passageways.
– Smooth muscle lining the passageways alternates contraction
and relaxation to propel matter through the alimentary canal.

Dilnessa F. 60
 Smooth Muscle cont…

• Integumentary system:
– Regulates blood flow to the superficial
dermis
– Allows for piloerection
• Respiratory system
– Alters the diameter of the airways and
changes the resistance to airflow
• Urinary system
– Sphincters regulate the passage of urine
– Smooth muscle contractions move urine
into and out of the urinary bladder
Dilnessa F. 61
 Smooth Muscle cont…

• Reproductive system
– Females
• Assists in the movement of the egg (and of
sperm) through the female reproductive
tract
• Plays a large role in childbirth
– Males
• Allows for movement of sperm along the
male reproductive tract.
• Allows for secretion of the non-cellular
components of semen.
• Allows for erection and ejaculation.
Dilnessa F. 62
 Smooth muscle cells
– Are smaller: 5-10um in diameter and 30-200um in length
– Are uninucleate: contain 1 centrally placed nucleus
– Lack any visible striations
– Lack T-tubules
– Have a scanty sarcoplasmic reticulum

• Smooth muscle tissue is innervated by the autonomic nervous

system unlike skeletal muscle which is innervated by the somatic
nervous system (over which you have control)
• Only the endomysium is present.
• No perimysium or epimysium.

Dilnessa F. 63
Smooth Muscle Contraction
• Begins with the opening of membrane channels.
• Channels may be ligand-gated (NTs, hormones,
metabolites), voltage-gated, or mechanically-gated
(stretch).
• Channels will allow significant calcium entry from the
ECF.
• Remember smooth muscle has little SR.
• Calcium binds to a regulatory molecule called
calmodulin and activates it.
• Activated calmodulin activates an enzyme called
Myosin Light Chain Kinase.

Dilnessa F. 64
Smooth Muscle Contraction

• Activated MLCK will add

a phosphate group to the
myosin of the thick
filament.
• This enables the myosin
to interact with actin.
– Tropomyosin is
present but not
blocking actin’s
myosin binding
sites
– Troponin is not
present
Dilnessa F. 65
 Smooth muscle relaxation:
Calcium is pumped out of the cell,
which decreases the amount of
active calmodulin which decreases
the amount of active MLCK which
decreases the number of
crossbridges.

Relaxation can occur subsequent to

contraction or at any time if anything
causes a decrease in the calcium
permeability of the smooth muscle
cell.

Why are calcium channel blockers

Dilnessa F.
given to people with hypertension? 66