NERVE-MUSCLE PHYSIOLOGY

Learning Objectives
• To describe muscle’s macro and micro structures
• To differentiate among types of muscle fibres
• To describe Nerve cells and type of nerve fibres
• To describe resting membrane potentials and Action potential.
• Stimulus-Response characteristics
• To be able to describe neuromuscular transmission
• To understand the processes involved in skeletal muscle contraction
and its energetics
• Muscle dysfunction

2
 Types of Muscle
• Muscle makes up 30-35% (in women) and 42-47% (in men) of
body mass.
Three types of muscle:

Skeletal muscle Cardiac muscle

Smooth muscle

3
Skeletal Muscle Tissue
(each skeletal muscle is an organ)
Cells
◼ Long and cylindrical, in bundles
◼ Multinucleate
◼ Obvious Striations

Skeletal Muscles-Voluntary
Connective Tissue Components:
◼ Endomysium-between fibers
◼ Perimysium-surrounds bundles
◼ Epimysium-surround whole muscle
◼ Attached to bones, fascia, skin
◼ Origin & Insertion
 Smooth Muscle Tissue
Cells
Single cells, uninucleate
No striations
Smooth Muscle-Involuntary
2 layers-opposite orientation (peristalsis)
Surrounds hollow organs, blood vessels
Connective Tissue Component
Endomysium: surrounds cells
Cardiac Muscle
Cells
◼ Branching, chains of cells
◼ Single Nucleated
◼ Striations
◼ Connected by Intercalated discs

Cardiac Muscle-Involuntary
Myocardium-heart muscle
◼ Pumps blood through vessels

Connective Tissue Component

◼ Endomysium: surrounding cells
 Skeletal Muscle Structure – Cellular Level 1

• A Skeletal muscle fiber is an individual muscle

cell
• Muscle fibers are long and narrow in shape
– Sarcolemma
• The plasma membrane of the muscle cell
• Surrounds the sarcoplasm
– Many nuclei (multi-nucleated)
• Located in the periphery of the muscle cell just beneath
the sarcolemma
 Skeletal Muscle Structure – Cellular Level 2

• Each muscle fiber contains various organelles

specifically designed to meet the needs of the
contractile skeletal muscle fiber
– Abundant mitochondria
• High demand for energy (ATP) required for muscle
contraction
– Myoglobin
• Protein with a high affinity for oxygen
• Transfers oxygen from the blood to the mitochondria of
the muscle cell
 Skeletal Muscle Structure – Cellular Level 3

• Each muscle fiber contains:

• Myofibrils – a cylindrical bundle of contractile proteins,
which are called Myofilaments, within a muscle fiber
– Located in the sarcoplasm of the muscle cell
• Myofilaments – the contractile protein filaments that
make up the Myofibrils
– Actin – thin filament
– Myosin – thick filament
 Skeletal Muscle Structure – Cellular Level 4

• Sarcoplasmic reticulum (SR)

– Saclike membranous network of tubules
• Elaborate form of smooth endoplasmic reticulum
– Surrounds each myofibril
– Contains terminal cisternae
• Located where the SR ends, which is near the area where actin
and myosin overlap
– The SR tubules and terminal cisternae store high
concentrations of calcium, which is important in the
process of skeletal muscle contraction
 Skeletal Muscle Structure – Cellular Level 5

• Transverse tubules (T-tubules)

– Closely associated with SR
– Connected to the sarcolemma
– Penetrate the sarcolemma into the interior of the muscle
cell (invaginations)
– Bring extracellular materials into close proximity of the
deeper parts of the muscle fiber
• SR and T-tubules Function
– Activate skeletal muscle contraction when the muscle cell
is stimulated by a nerve impulse
– Transmit nerve impulses from the sarcolemma to the
myofibirls
Skeletal Muscle Structure – Molecular Level 1

• Sarcomere
– Smallest contractile unit of the muscle fiber
– Arrangement of Myofilaments
• Alternating bands of light and dark areas
• Due to the organization of the actin and myosin
– Striated appearance
 Sarcomere Components
• Z-lines = borders of the sarcomere
– Perpendicular to long axis of the muscle fiber
– Anchor thin myofilaments (actin)
• M-lines
– Perpendicular to long axis of the muscle fiber
– Anchor thick myofilaments (myosin)
 Sarcomere Components
• A-Bands
• Dark area where actin and myosin overlap
• Equal to the length of the thick myofilaments (myosin)
• Contains the H-Zone
– Lighter area within the A-Band that contains only myosin
– The M-Line is located with the H-zone
• I-Bands
• Light area composed of actin only
• Contains the Z line, which is the boarder of the
sarcomere
– Actin is directly attached the Z-Line
– Appears as a darker line through the I-Band.
Skeletal Muscle Structure – Molecular Level 2

• Actin
– G-actin (globular actin) = the basic component of each
actin myofilament
• Contains myosin binding sites
– The actin myofilament consists of two strands of G-actin
molecules
• The two strands of G-action molecules are twisted together with
two regulatory proteins:
– tropomyosin
– troponin
Skeletal Muscle Structure – Molecular Level 3

• Tropomyosin
– Rod-shaped protein that occupies the groove between the
twisted strand of actin molecules
– Blocks the myosin binding sites on the G-actin molecules
• Troponin
– A complex of three globular proteins.
• One is attached to the actin molecule
• One is attached to tropomyosin
• One contains a binding site for calcium
Skeletal Muscle Structure – Molecular Level 4

• Myosin
– Crossbridges
• Composed of a rod-like tail and two globular heads
– The tails form the central portion of the myosin myofilament
– The two globular headsface outward and in opposite
directions
• Interact with actin during contraction.
• Contain binding sites for both actin and ATP
– The enzyme ATP-ase is located at the ATP binding site for
hydrolysis of ATP
Skeletal Muscle Structure – Molecular Level 5

• Titin
– Connects myosin to the Z-lines in the sarcomere
– It is very elastic
• Able to stretch up to 3 times its resting length
– Important molecule because it is responsible for
muscle flexibility
 Types of Skeletal Muscle Fibers
• Not all muscle fibers are the same physiologically
• Muscles vary depending on:
– The predominant pathway utilized to synthesize ATP
• Oxidative fibers - predominantly aerobic pathways
– Oxidative phosphorylation in the mitochondria
– Fatigue-resistant fibers
• Glycolytic fibers – predominantly anaerobic pathways
– Glycolysis in the sarcoplasm
– Fatigable fibers
– The amount of myoglobin
• Red fibers - high amounts of myoglobin
• White fibers - small amounts of myoglobin
– Efficiency of ATPase
• Fast twitch fibers - decompose ATP rapidly
• Slow twitch fibers - decompose ATP slowly
 Types of Skeletal Muscle Fibers 2
• Slow-twitch fatigue-resistant fibers
– Slow oxidative fibers, or red muscle fibers.
– Contain abundant myoglobin giving them their red color.
– Slow acting ATPase enzymes
– Abundant mitochondria
• Depend upon aerobic pathways for production of ATP
– Endurance type muscles
• Able to deliver strong, prolonged contractions.
• Examples:
– Postural muscles - spinal extensors
– Anti-gravity muscles - calf muscle
 Types of Skeletal Muscle Fibers 3
• Fast-twitch fatigable fibers
– Fast glycolytic fibers, or white muscle fibers.
– Contain small amounts of myoglobin
– Fast acting ATPase enzymes
• Allows the muscle fiber to contract rapidly
– Few mitochondria
• Contract for limited periods of time because fatigue rapidly
– Plenty of glycogen
• Depends on anaerobic metabolism
– Extensive sarcoplasmic reticulum
• Rapidly releases and stores calcium ions contributing to rapid contractions
– Best suited for short duration, high intensity contractions
 Types of Skeletal Muscle Fibers 4
• Intermediate Fibers
– Fast-twitch fatigue-resistant fibers
• Fast glycolytic fibers
• Pale muscle fibers
– They lie between the red and white fibers
 Types of Skeletal Muscle Fibers 5
• Most of the body's muscles contain a mixture of fiber
types.
• It is the motor nerve that innervates the muscle cell that
determines its type
– Therefore, all of the muscle cells in a single motor unit are of
the same type
– Motor Unit – a motor neuron and all of the muscle fibers it
innervates
• Examples:
– Running – the motor nerve stimulates the motor units
containing fast-twitch fibers.
– Posture – the motor nerve stimulates the motor units
containing slow-twitch fibers.
 Types of Skeletal Muscle Fibers 6
• Slow twitch fibers are recruited first
– This is because they are found in small motor
units
• Fast twitch fibers are recruited last
– This is because they are found in large motor units
 Types of Skeletal Muscle Fibers
• People are genetically predisposed to have
relatively more of one fiber type than another
– People who excel at marathon running have
higher percentages of slow twitch fatigue resistant
muscle fibers
– People who excel at sprinting have higher
percentages of fast twitch fatigable fibers
 Smooth Muscle

• In comparison to skeletal muscle fibers

– Smooth muscle fibers are shorter and thinner
– They have a single, centrally located nucleus
– Lack striations
• Although smooth muscle fibers do contain actin and myosin, the
filaments are thin and randomly arranged so that it lacks striations
– No T-tubules
– A poorly developed sarcoplasmic reticulum
 Smooth Muscle 2
• Smooth muscle fibers contract in a similar manner to
skeletal muscles with a few important functional
similarities and differences.
– Similarities
• Both contractile mechanisms depend on the action of actin and
myosin;
• Both are triggered by membrane impulses and the release of
calcium ions; and
• Both require ATP.
 Smooth Muscle 3
– Differences in smooth muscle include
• Actin has no troponin, the protein that binds to actin in skeletal
muscle. Rather smooth muscle has a calcium binding protein
called calmodulin. This protein activates the actin and myosin
crossbridge formation.
• Most of the calcium required for contraction comes into the cell by
diffusion from the extracellular fluid.
• Smooth muscle is more resistant to fatigue and produces a slower,
longer lasting contraction than skeletal muscle.
• It is more energy efficient than skeletal muscle in that it can
maintain a more forceful contraction for a longer period of time
with the same amount of ATP.
 Smooth Muscle 4
• Autonomic nervous system control
– Unconscious control of smooth muscle contraction
– Nuerotransmitters
• Acetylcholine (as in skeletal muscle)
• Norepinephrine.
• Neurotransmitters for smooth muscle can be either excitatory (cause
muscle contraction), or inhibitory (prevent muscle contraction) depending
on the receptor on the smooth muscle cell membrane. Whereas, the
neurotransmitter for skeletal muscle is always excitatory.
– Smooth muscle is also stimulated by certain hormones such as
oxytocin, which stimulates smooth muscle contraction in the walls of
the uterus during childbirth.
 Smooth Muscle 5
• Multiunit smooth muscle
– Fibers are not very well organized
• Occur as separate fibers scattered throughout the
sarcoplasm rather than in sheets.
– Requires stimulation by a motor nerve impulse
from the autonomic nervous system.
– This type of smooth muscle is found in the irises
of the eyes, arrector pili muscles, blood vessels,
and large airways of the lungs
 Smooth Muscle 6
• Single Unit Smooth Muscle
– Also called Visceral Smooth Muscle because it is found in the walls
of the hollow visceral organs such as the stomach, intestines, urinary
bladder and uterus.
– More common of the two types of smooth muscle.
– The muscle fibers are organized into sheets of cells held in close
contact by gap junctions.
– Organized into two layers:
• Longitudinal layer
– Outer layer directed longitudinally along the length of the structure.
– Contraction of this layer causes the structure to dilate and shorten
• Circular layer
– Inner layer arranged circularly around the structure.
– Contraction of this layer causes the structure to constrict and elongate.
 Smooth Muscle 7
• Intrinsic Control of Smooth Muscle Contraction
• Myogenic Response
• Smooth muscle is stimulated to contract when it is
stretched
• Smooth muscle is able to distend, or stretch, without
great increases in tension or tightness
– Allows hollow organs to be filled
• When the smooth muscle reaches is stretching
capacity, it will contract and force the contents out
» Such as occurs in the intestines or urinary bladder.
 Cardiac Muscle
• Found only in the heart
• Composed of interconnecting, branching fibers that are
striated
• Each cell has a single nucleus similar to smooth muscle
• Contains actin and myosin similar to smooth muscle.
• Abundant mitochondria
– Depends on aerobic metabolism
– It cannot sustain an oxygen debt and still function efficiently
• No motor units
– Not every cardiac muscle cell is innervated by a nerve in order to
stimulate contraction
 Cardiac Muscle 2
• Extensive system of T-tubules
– Release large quantities of calcium ions
• Well developed sarcoplasmic reticulum
– Terminal cisternae contain less calcium than in skeletal muscle
– Strength of the cardiac muscle contraction depends largely on the
influx of calcium from the extracellular space in addition to that
released from the T-tubules and sarcoplasmic reticulum
• Contains intercalated disks
– Membrane junctions that hold adjacent cells together and transmit
the contraction force to each cell
• Gap Juntions
– Most important intercellular junction that allow interchange and
communication between the sarcoplasm of connected cardiac muscle
cells
 Cardiac Muscle 3

• Communication between Cardiac Muscle Cells is

important to allow the nerve impulse to rapidly
travel from cell to cell to stimulate contraction
– Stimulation of part of the cardiac muscle cell results in
impulses sent across the entire area of the heart muscle
tissue
• All-or-none Response
– The entire heart muscle contracts as a unit, or in syncytium
 Cardiac Muscle 4

• Two syncytium are in heart:

– The atrial syncytium and the ventricular syncytium
– They are almost completely separated from each other
by fibrous tissue
• The all-or-none response applies to the entire
syncytium
• Either both atria contact, or both do not contract at all
• Either both ventricles contact, or both do not contract at all
 Cardiac Muscle 5
• Cardiac Muscle Contraction
• Plateau Phase
– The prolonged depolarization in cardiac muscle due to Calcium influx
from the extra-cellular fluid
– The prolonged plateau phase prevents tetany, or prolonged
contractions, that would interfere with the pumping ability of the
heart
• Refractory Period
– Due to the calcium influx in cardiac muscle, there is a prolonged
absolute refractory period of cardiac muscle lasting about 250 msec.
• Much longer than skeletal muscle which lasts about 1-2 msec.
• Repolarization
– Calcium is pumped back into sarcoplasmic reticulum and out of cell to
the extracellular space.
 Cardiac Muscle 6

• Cardiac muscle is self-exciting

– It is able to stimulate itself to contract
• Cardiac muscle is autorhythmic
– It contracts in a periodic manner
• Autorhythmicity causes the automatic contraction
and relaxation of the heart
– Known as the heartbeat.
 Cardiac Muscle 7
• Autorhythmicity
– Ability of cardiac muscle to repeatedly and rhythmically contract
without external stimulation
• Due to the presence of Pacemaker Cells in the heart
– Specialized smooth muscle cells that depolarize spontaneously at
regular intervals causing excitation of the muscle cells without
nervous system stimulation
– The spontaneous impulses travel into the surrounding muscle
tissue through gap junctions that connect the cell membranes of
adjacent muscle fibers, thus allowing the heart to contract as a
coordinated unit
 NERVE CELLS
• 2 types of cells in the nervous system:
– Neurons.
– Supporting cells.

• Nervous system is divided into:

– Central nervous system (CNS):
• Brain.
• Spinal cord.
– Peripheral nervous system (PNS):
• Cranial nerves.
• Spinal nerves.
 Neurons
• Basic structural and functional units of the nervous
system.
– Cannot divide by mitosis.
• Respond to physical and chemical stimuli.
• Produce and conduct electrochemical impulses.
• Release chemical regulators.
• Nerve:
– Bundle of axons located outside CNS.
• Most composed of both motor and sensory fibers.
 Neurons 2
• Cell body (perikaryon):
– “Nutrition center.”
– Cell bodies within CNS clustered into nuclei, and in PNS in ganglia.
• Dendrites:
– Provide receptive area.
– Transmit electrical impulses to cell body.
• Axon:
– Conducts impulses away from cell body.
– Axoplasmic flow:
• Proteins and other molecules are transported by rhythmic contractions to
nerve endings.
– Axonal transport:
• Employs microtubules for transport.
• May occur in orthograde or retrograde direction.
 Functional Classification of Neurons
• Based upon direction
impulses conducted.
• Sensory or afferent:
– Conduct impulses from
sensory receptors into
CNS.
• Motor or efferent:
– Conduct impulses out of
CNS to effector organs.
• Association or
interneurons:
– Located entirely within the
CNS.
– Serve an integrative
function.
 Structural Classification of Neurons
• Based on the number
of processes that
extend from cell
body.
– Pseudounipolar:
• Short single process
that branches like a T.
– Sensory neurons.
– Bipolar neurons:
• Have 2 processes.
– Retina of the eye.
– Multipolar:
• Have several dendrites
and 1 axon.
– Motor neuron.
SUPPORTING CELLS
 DIFFUSION POTENTIALS
• Concept of Diffusion Potentials : A diffusion potential is
the potential difference generated across a membrane
when a charged solute ( an ion) diffuses down its
concentration gradient.

• Equilibrium Potentials: This is the diffusion potential

that exactly balances or opposes the tendency for
diffusion down the concentration difference. At
electrochemical equilibrium, the chemical and
electrical driving forces acting on an ion are equal and
opposite, and no further net diffusion occurs.
 DIFFUSION POTENTIALS
• The Nernst Equation is used to calculate the
equilibrium potential for an ion at a given
concentration difference across a membrane,
assuming the membrane is permeable to that
ion.
• EMF = ± 61 log Concentration inside
Concentration outside
ENa = + 65mV
ECa = + 120 mV
EK = -85mV
ECl = -90mV
 RESTING MEMBRANE POTENTIAL(RMP)

• RMP is the potential difference that exists across

the membrane of excitable cells, such as nerve
and muscle, in the period between action
potentials.
• The RMP is established by diffusion potentials,
which results from concentration differences
from various ions across the cell membrane.
• This conc. Diff. has been established by primary
and secondary active transport mechanisms.
 RESTING MEMBRANE POTENTIAL(RMP)
Cont.
• Each permeant ion attempts to drive the membrane
potential toward its own equilibrium potential. Ions
with the greatest permeability or conductance exerts
the greatest contribution to RMP and those with lower
permeability will make little or no contribution.

• The RMP of excitable cells falls between -70 to -80mV.

This potential is closer to those of potassium and
Chloride because this ions are most permeable at rest.
On the other hand, the RMP is far from those of
Calcium and Sodium because the permeability to this
ions at rest is low.
ROLE OF SODIUM-POTASIUM ATPase IN CREATING RMP

• 1. The electrogenic contribution of pumping 3 Na

ions out of the cell for every 2 potassium ions
pumped into the cell.

• 2. The second important indirect function is the

maintenance of the concentration gradient of
potassium across the cell membrane, which then
is responsible for the diffusion potential that
drives the membrane potential toward the K
equilibrium potential.
 NERVE FIBER TYPES IN A MIXED NERVE
Group Fibre Conduction Modality/Source
diameter velocity (m/s)
(µm)
A
Alpha 12-20 70-120 Proprioceptor, somatic motor
Beta 5-12 30-70 Tactile, Pressure
Gamma 3-6 15-30 Motor to muscle spindle
Delta 2-5 12-15 Pain, Temperature

B : Sympathetic 1.5-3 3-15 Pre-ganglionic autonomic

preganglionic

C
Dorsal root 0.4-1.2 0.5-2 Pain
Sympathetic 0.3-1.3 0.7-2.3 Post ganglionic autonomic
postganglionic
 Electrical Activity of Axons
• All cells maintain a resting membrane potential
(RMP):
– Potential voltage difference across membrane.
• Largely the result of negatively charged organic molecules within
the cell.
• Limited diffusion of positively charged inorganic ions.
– Permeability of cell membrane:
• Electrochemical gradients of Na+ and K+.
• Na+/K+ ATPase pump.
• Excitability/irritability:
– Ability to produce and conduct electrical impulses.
 Electrical Activity of Axons (continued)

• Increase in membrane permeability for specific ion can be

measured by placing 2 electrodes (1 inside and 1 outside the
cell).
• Depolarization:
– Potential difference reduced (become more positive).
• Repolarization:
– Return to resting membrane potential (become more negative).
• Hyperpolarization:
– More negative than RMP.
 Ion Gating in Axons
• Changes in membrane potential caused by ion flow through
ion channels.
• Voltage gated (VG) channels open in response to change in
membrane potential.
– Gated channels are part of proteins that comprise the channel.
• Can be open or closed in response to change.
– 2 types of channels for K+:
• 1 always open.
• 1 closed in resting cell.
– Channel for Na+:
• Always closed in resting cells.
– Some Na+ does leak into the cells.
Ion Gating in Axons
 Action Potentials (APs)
• Stimulus causes depolarization to threshold.
• VG Na+ channels open.
– Electrochemical gradient inward.
• + feedback loop.
– Rapid reversal in membrane potential from –70 to + 30
mV.
– VG Na+ channels become inactivated.
• VG K+ channels open.
– Electrochemical gradient outward.
– - feedback loop.
– Restore original RMP.
Action Potentials (APs)
 Action Potentials (APs) (continued)

• Depolarization and repolarization occur via diffusion, do not

require active transport.
– Once AP completed, Na+/K+ ATPase pump extrudes Na+, and recovers
K+.
• All or none:
– When threshold reached, maximum potential change occurs.
– Amplitude does not normally become more positive than + 30 mV
because VG Na+ channels close quickly and VG K+ channels open.
– Duration is the same, only open for a fixed period of time.
• Coding for Stimulus Intensity:
– Increased frequency of AP indicates greater stimulus strength.
• Recruitment:
– Stronger stimuli can activate more axons with a higher threshold.
 Refractory Periods
• Absolute refractory period:
– Axon membrane is incapable of
producing another AP.
• Relative refractory period:
– VG ion channel shape alters at
the molecular level.
– VG K+ channels are open.
– Axon membrane can produce
another action potential, but
requires stronger stimulus.
 Cable Properties of Neurons
• Ability of neuron to transmit charge through
cytoplasm.
• Axon cable properties are poor:
– High internal resistance.
– Many charges leak out of the axon through membrane.
• An AP does not travel down the entire axon.
• Each AP is a stimulus to produce another AP in the
next region of membrane with VG channels.
Conduction in an Unmyelinated Axon
• Cable spread of
depolarization with influx
of Na+ depolarizes the
adjacent region
membrane, propagating
the AP.
• Conduction rate is slow.
– AP must be produced at
every fraction of
micrometer.
• Occurs in 1 direction;
previous region is in its
refractory period.
 Conduction in Myelinated Axon
• Myelin prevents movement of
Na+ and K+ through the
membrane.
• Interruption in myelin (Nodes
of Ranvier) contain VG Na+ and
K+ channels.
• AP occurs only at the nodes.
– AP at 1 node depolarizes
membrane to reach
threshold at next node.
• Saltatory conduction (leaps).
– Fast rate of conduction.
 STIMULUS-RESPONSE CHARACTERISTICS
• ALL OR NONE LAW
Provided that threshold is reached, the magnitude of an
action potential in a neuron is always the same and is
independent of the stimulus.

In Skeletal Muscles, when the muscle is stimulated there

is a twitch response, which increases in height and
reaches a maximum force for contraction. Beyond this,
further increase in stimulus strength does not increase
contraction, this is because all the muscle fibers are now
stimulated and further increase in stimulus strength does
not produce further contraction.
Recruitment of motor fibers and all or none law

A B C D E
The Initial response (A) is to threshold stimulus
and as the stimulus strength increases (B,C), motor
fibers are recruited. At maximum response (D)
further increases in stimulus strength does not
increase contractile force. At this point the all or
none law is obeyed i.e. when stimulated the
 Strength-Duration Curve
• The stimulus that is usually applied to an
excitable tissue is a square-wave pulse. When
a stimulus current of strength I, is applied to
an excitable tissue, it requires a finite time t,
before it can induce a response.

• If the threshold current strength I is plotted

against the time required for its application(t)
before a response is obtained, a curve-the
strength-duration curve is obtained.
 Rheobase is the minimum current just
sufficient to excite a tissue

The Utilization time is the time for

Square wave stimulus
action of rheobasal current

Chronaxie is the time required for

Current twice rheobasal current to act in order
strength to produce a response.
(I)

Chronaxie is an index of excitability of

2R the tissue such that the more excitable
R
the tissue the less the chronaxie.

Time (t)
Chronaxie Utilization time
Strength-duration curve (R= Rheobase)
 SYNAPSE
• Functional connection between a neuron and
another neuron or effector cell.
• Transmission in one direction only.
• Axon of first (presynaptic) to second
(postsynaptic) neuron.
• Synaptic transmission is through a chemical
gated channel.
• Presynaptic terminal (bouton) releases a
neurotransmitter (NT).
 Electrical Synapse
• Impulses can be regenerated
without interruption in
adjacent cells.
• Gap junctions:
– Adjacent cells electrically
coupled through a channel.
– Each gap junction is composed
of 12 connexin proteins.
• Examples:
– Smooth and cardiac muscles,
brain, and glial cells.
 Chemical Synapse
• Terminal bouton is
separated from
postsynaptic cell by
synaptic cleft.
• NTs are released from
synaptic vesicles.
• Vesicles fuse with axon
membrane and NT
released by exocytosis.
• Amount of NTs released
depends upon
frequency of AP.
 Synaptic Transmission
• NT release is rapid because many vesicles form
fusion-complexes at “docking site.”
• AP travels down axon to bouton.
• VG Ca2+ channels open.
– Ca2+ enters bouton down concentration gradient.
– Inward diffusion triggers rapid fusion of synaptic vesicles
and release of NTs.
• Ca2+ activates calmodulin, which activates protein
kinase.
• Protein kinase phosphorylates synapsins.
– Synapsins aid in the fusion of synaptic vesicles.
 Synaptic Transmission (continued)

• NTs are released and diffuse across synaptic cleft.

• NT (ligand) binds to specific receptor proteins in
postsynaptic cell membrane.
• Chemically-regulated gated ion channels open.
– EPSP: depolarization.
– IPSP: hyperpolarization.
• Neurotransmitter inactivated to end transmission.
 Chemical Synapses
• EPSP (excitatory
postsynaptic
potential):
– Depolarization.
• IPSP (inhibitory
postsynaptic
potential):
– Hyperpolarization
 EPSP
• No threshold.
• Decreases resting
membrane potential.
– Closer to threshold.
• Graded in magnitude.
• Have no refractory
period.
• Can summate.
 Synaptic Integration
• EPSPs can
summate,
producing AP.
– Spatial summation:
• Numerous
boutons converge
on a single
postsynaptic
neuron (distance).
– Temporal
summation:
• Successive waves
of
neurotransmitter
release (time).
Comparism of Action potential and Excitatory
postsynaptic potential
 Synaptic Inhibition
• Presynaptic inhibition:
– Amount of excitatory NT
released is decreased by
effects of second neuron,
whose axon makes synapses
with first neuron’s axon.
• Postsynaptic inhibition
• (IPSPs):
– No threshold.
– Hyperpolarize postsynaptic
membrane.
– Increase membrane
potential.
– Can summate.
– No refractory period.
 Synaptic Inhibition Contd.
• The neurotransmitters glycine and GABA hyperpolarize
the postsynaptic membrane; that is, they make the
inside of the membrane more negative than it is at
rest. (from − 70 mV to, for example, − 85 mV)

• Hyperpolarizations produced by neurotransmitters are

therefore called inhibitory postsynaptic potentials
(IPSPs),. The inhibition produced in this way is called
postsynaptic inhibition.

• Postsynaptic inhibition in the brain is produced by

GABA; in the spinal cord it is mainly produced by
glycine (although GABA is also involved).
 Neuromuscular Transmission
SPERCIFIC OBJECTIVES:
• Describe the sequence of electrical and chemical events at
the neuromuscular junction during transmission of an
action potential.
• Provide some of the evidence that acetylcholine (ACh) is
released, and that the release is quantal in nature.
• Describe the ionic mechanisms of the endplate potential
(EPP), including the types of ion channels involved.
• Consider the disorder Myasthenia Gravis, and the
rationale for treatment with inhibitors of
acetylcholinesterase.
Sequence of Events in Neuromuscular Transmission
(1)
Presynaptic Events
1. Action potential (AP) is initiated in the presynaptic
motor neuron (MN) and invades the endplate region
2. Depolarization of MN terminal boutons, resulting in the
opening of voltage-dependent calcium channels
3. Influx of Ca2+, down its concentration gradient
4. Rise of intracellular free [Ca2+] initiates fusion of
vesicles containing acetylcholine (ACh) to the
membrane of the terminal boutons, resulting in
exocytosis of ACh
5. Diffusion of ACh across synaptic cleft to the muscle cell
Sequence of Events in Neuromuscular Transmission
(2)
Postsynaptic Events
6. Binding of ACh to nicotinic ACh-receptors at endplate
7. Receptor binding causes opening of cation channels,
leading to influx of Na+ (ACh is then degraded by
acetylcholinesterase present in the synaptic cleft)
8. The resulting depolarization of muscle cell membrane at
the endplate is referred to as the endplate potential (EPP)
9. The local depolarization causes adjacent regions to be
depolarized, causing an AP in the muscle cell membrane
10. AP spreads out in all directions from the endplate,
propagates along muscle cell, initiating contraction
 Motor End Plate (continued)
Each vesicle
contains ~5000
ACh molecules.
1 vesicle=1
quanta
Each vesicle is
~50 nm diameter

Postsynaptic membrane: Synaptic cleft between

Clusters of nicotinic ACh nerve and muscle cells
receptors in the junctional Size? A 50 to 100 nm
folds gap.
 Exocytosis at the Terminal Boutons

Resting nerve with

abundant vesicles
Synaptic cleft is
50 to 100 nm

Stimulate nerve
and observe Time for
fusion of diffusion of ACh
vesicles with is ~0.5 ms
membrane.
Vesicle
exocytosis
releases ACh
into synaptic
 End Plate Potentials
• From mini-EPP, to summation and EPP to Action Potential
Record
Membrane
potential
of muscle

Stimulate nerve

Vm Vm Vm
0.5 5 5
mV mV Stimulate mV Stimulate
nerve nerve
Miniature EPP EPP EPP brings membrane
(spontaneous, 1 vesicle (evoked, ~200 quanta) to threshold and initiates
aka 1 quantum) action potential
 Summary of Neuromuscular
Transmission
Action potential invades presynaptic terminal

Opening of Ca2+ channels leads to

influx of Ca2+ (extracellular Ca2+ is
essential)
+ + Vesicles fuse and release ACh into
cleftACh diffuses across synaptic
cleft

ACh activates cation

ACh-activated channel is channels to cause depolarization
+ + of the endplate.
permeable to both Na+ and K+,
so the reversal potential is a
mixture of the two
 Summary of Neuromuscular
Transmission

ACh is destroyed by
+ + acetylcholinesterase
enzymes in the synaptic
cleft

In healthy muscle, an AP in the

Depolarization of the end plate motor neuron ALWAYS
+ +
initiates an action potential
that spreads over muscle cell
activates an AP in the muscle,
leading to contraction (safety
factor is ~2).
 Pharmacology of the End Plate
Potential
Curare Neostigmine
•Blocker of nicotinic receptors •Blocker of
•Plant extract used to induce cholinesterases
paralysis •Component of nerve
•Must be careful with patients, as gases and
they may feel pain but cannot insecticides
show it
Control EPP + Neostigmine
Vm Vm
5 5
mV + Curare mV
Control EPP
Stimulate Stimulate
nerve nerve
 Clinical Case:
• A patient presents with muscle weakness, and fatigues
easily

Findings shows that there was:

• No muscle atrophy
• Normal nerve conduction
• muscle response to repeated stimulation is decreased
• muscle response with repeated direct stimulation of the muscle is
normal
• When muscle biopsy is studied, small MEPPs and EPPs are
observed.
• Muscle weakness improves with neostigmine (tensilon has briefer
duration, so is better in the clinical setting)
 Tentative Diagnosis: Myasthenia Gravis
• Myasthenia Gravis is an autoimmune disease in which patients
develop antibodies against nicotinic ACh receptors.

• Thus, the amplitudes of MEPPs and EPPs are reduced (since

there will be less depolarization for the same amount of released
ACh) and the muscle membrane may not be depolarized
sufficiently to fire an action potential.

• Treatment is to give an acetylcholinesterase inhibitor to prolong

and increase the action of ACh at the available receptors and to
restore the muscle action potential.
The Mechanism of Force Generation in Muscle
Muscle relaxation
• Ach is removed from the receptors by
acetylcholinesterase
• Ligand-gated Na+channels close
• Na/K pumps reestablish the RMP
• Ca++ ions leave troponin and are brought back into
the cisternae (this process needs energy)
• Tropomyosin moves back over the actin active site
• The myosin heads release their binding to actin
• The filaments passively move back into resting
position
Drugs that affect the neural control of skeletal muscle
 Muscle contraction: Mechanical events

1. stimulation → 1 twitch

• Muscle twitch: 3 phases:

- latent phase
- contraction phase
- relaxation phase

☻ do not confuse the AP and

the twitch!!!
 Events during the twitch
• Latent phase: from when
stimulus was applied to the
beginning contraction. i.e. when
myosin binds to actin active site
• Contraction phase: beginning to
end of muscle tension → myosin
heads slide along the actin
filaments
• Relaxation phase: peak tension to
no tension → Ca++ ions moved
back into the cisternae,
tropomyosin moves back over
actin, myosin head release actin
and the filaments move back into
resting position
 Tetany
• Sustained contraction of a muscle
• Result of a rapid succession of nerve impulses
 Effect of consecutive stimuli: Treppe

• Treppe: gradual
increase in contraction
intensity during
sequential stimulation

• Might be due to calcium

ions accumulating in
the cytoplasm with
each stimulation

Figure 12.15
 Refractory Period
• Brief period of time in which muscle cells will
not respond to a stimulus
 Muscle fatigue
• Muscle fatigue: a decline in
the ability of the muscle to
sustain the strength of
contraction

• Causes:
- rapid build-up of lactic acid
- decrease in oxygen supply
- decrease in energy supply
(glucose, glycogen, fatty-
acids)
- Decreased neurotransmitter
at the synapse
 ENERGETICS OF MUSCLE CONTRACTION

Muscle contraction depends on energy supplied by

ATP. Most of this energy is required to actuate the
walk-along mechanism by which the cross-bridges
pull the actin filaments. This ATP is also used for
(1) pumping calcium ions from the sarcoplasm into
the sarcoplasmic reticulum after the contraction is
over, and
(2) pumping sodium and potassium ions through the
muscle fiber membrane to maintain appropriate ionic
environment for propagation of muscle fiber action
potentials
Energetics of muscle contraction (2)
Therefore, the concentration of ATP in the muscle
fiber, is sufficient to maintain full contraction for only
1 to 2 seconds at most. The ATP is split to form ADP,
which transfers energy from the ATP molecule to the
contracting machinery of the muscle fiber
Subsequently the ADP is rephosphorylated to form
new ATP within another fraction of a second, which
allows the muscle to continue its contraction. There
are 3 major means by which ATP is rephosphorylated.
They include:
 Energetics of muscle contraction (3)
• 1. The substance phosphocreatine: The
high-energy phosphate bond of
phosphocreatine has a slightly higher amount
of free energy than that of each ATP bond.

• Therefore, phosphocreatine is instantly

cleaved, and its released energy causes
bonding of a new phosphate ion to ADP to
reconstitute the ATP.
Energetics of muscle contraction (4)
Total amount of phosphocreatine in the
muscle fiber is also very little— it is only
about five times as great as the ATP.

Therefore, the combined energy of both the

stored ATP and the phosphocreatine in the
muscle is capable of causing maximal
muscle contraction for only 5 to 8 seconds.
 Energetics of muscle contraction (5)
2. The second important source of energy, which
is used to reconstitute both ATP and
phosphocreatine, is “glycolysis” of glycogen
previously stored in the muscle cells.

Rapid enzymatic breakdown of the glycogen to

pyruvic acid and lactic acid liberates energy that is
used to convert ADP to ATP; the ATP can then be
used directly to energize additional muscle
contraction and also to re-form the stores of
phosphocreatine.
 Energetics of muscle contraction (6)
The importance of this glycolysis mechanism is twofold.
First, the glycolytic reactions can occur even in the
absence of oxygen, so that muscle contraction can be
sustained for many seconds and sometimes up to more
than a minute, even when oxygen delivery from the
blood is not available.

Second, the rate of formation of ATP by the glycolytic

process is about 2.5 times as rapid as ATP formation in
response to cellular foodstuffs reacting with oxygen.
However, so many end products of glycolysis accumulate
in the muscle cells that glycolysis also loses its capability
to sustain maximum muscle contraction after about 1
minute
 Energetics of muscle contraction (7)
3. The third and final source of energy is
oxidative metabolism. This means combining
oxygen with the end products of glycolysis and
with various other cellular foodstuffs to
liberate ATP.

More than 95 per cent of all energy used by

the muscles for sustained, longterm
contraction is derived from this source. The
foodstuffs that are consumed are
carbohydrates, fats, and protein.
 Energetics of muscle contraction (8)
For extremely long-term maximal muscle
activity—over a period of many hours—by far
the greatest proportion of energy comes from
fats, but for periods of 2 to 4 hours, as much as
one half of the energy can come from stored
carbohydrates.
 MUSCLES DYSFUNCTION – MYOPATHY
Myopathy is a muscular disorder in which the dysfunction
of muscle fiber leads to muscular weakness.

Common diseases of skeletal muscles are:

1. Muscular dystrophy
2. Diseases involving muscle tone
3. Myasthenia gravis
4. LambertEaton syndrome
5. McArdle disease
6. Mitochondrial myopathy
7. Nemaline myopathy
 Muscle Dysfunction-continued
1. Muscular dystrophy: This is a disease characterized by
progressive degeneration of muscle fibers, without the
involvement of nervous system. The muscles fail to
regenerate, resulting in progressive weakness and
confinement to a wheelchair.

Duchenne Muscular Dystrophy : This is a sex-linked

recessive disorder. It is due to the absence of a gene
product called dystrophin in the X chromosome.
Dystrophin is necessary for the stability of sarcolemma.
This disease is characterized by degeneration and
necrosis of muscle fibers. The degenerated muscle fibers
are replaced by fat and fibrous tissue.
 Muscle Dysfunction-continued
Becker Muscular Dystrophy
Becker muscular dystrophy is also a sex-linked
disorder. It occurs due to the reduction in
quantity or alteration of dystrophin. Common
features of this disorder are slow progressive
weakness of legs and pelvis,
pseudohypertrophy of calf muscles, difficulty
in walking and fatigue.
 Muscle Dysfunction-continued
2. Diseases involving muscle tone
a.Hypertonia : This is a muscular disease characterized
by increased muscle tone and inability of the muscle to
stretch. It occurs in upper motor neuron lesion.
During upper motor neuron lesion, inhibition of lower
motor neurons (gamma motor neurons in the spinal
cord) is lost. This causes the exaggeration of lower
motor neuron activity, resulting in hypertonia.

In children, hypertonia is associated with cerebral palsy.

(permanent disorder caused by brain damage, which
occurs at or before birth and is characterized by muscular
impairment).
 Hypertonia and spasticity

Spasticity is a motor disorder characterized by

stiffness of the certain muscles due to
continuous contraction.
Hypertonicity is one of the major symptoms
of spasticity. Paralysis (complete loss of
function) of the muscle due to hypertonicity is
called spastic paralysis.
 Muscle Dysfunction-continued
Diseases involving muscle tone
b. Hypotonia : this is the muscular disease characterized
by decreased muscle tone. The tone of the muscle is
decreased or lost. Muscle offers very little resistance to
stretch. Muscle becomes flaccid (lack of firmness) and the
condition is called flaccidity.

The major cause for hypotonia is lower motor neuron

lesion. The paralysis of muscle with hypotonicity is called
flaccid paralysis and it results in wastage of muscles.
Hypotonia may also occur because of central nervous
system dysfunction, genetic disorders or muscular
disorders.
Clinical conditions associated with hypotonia are:
i. Down syndrome (chromosomal disorder,
characterized by physical and learning disabilities)
ii. Myasthenia gravis
iii. Kernicterus (brain damage caused by jaundice in
infants)
iv. Congenital cerebellar ataxia (incoordination)
v. Muscular dystrophy
vi. Congenital hypothyroidism
vii. Hypervitaminosis D
viii. Rickets
ix. Infant botulism (paralysis due to botulinum toxin).
 Muscle Dysfunction-continued
Diseases involving muscle tone
c. Myotonia is a congenital disease characterized by
continuous contraction of muscle and slow relaxation
even after the cessation of voluntary act. It is caused
by mutation of genes of channel proteins in
sarcolemma. The main feature of this disease is the
muscle stiffness, which is sometimes referred as
cramps.
TYPES: i. Becker-type myotonia or generalized myotonia
: an autosomal recessive disorder produced by defective
genes contributed by both the parents
ii. Thomsen-type myotonia is relatively rare and it is an
autosomal recessive disorder produced by defective gene
contributed by one parent.
 Muscle Dysfunction-continued
3. MYASTHENIA GRAVIS : This is an autoimmune
disease of neuromuscular junction caused by
antibodies to cholinergic receptors. Autoantibodies
(IgG autoantibodies) develop and fight against the
receptors of acetylcholine
Symptoms: Muscles easily affected are muscles of the
neck, limbs, eyeballs and eyelid movements
Common symptoms are: Slow and weak muscular
contraction, Inability to maintain the prolonged
contraction of skeletal muscle, fatigue an weakness ,
double vision and droopy eyelids, difficulty in
swallowing due to weakness of throat muscles and
difficulty in speech .
 Muscle Dysfunction-continued
4. Lamberteaton syndrome: This is a disorder of
neuromuscular junction caused by development of
antibodies against calcium channel in the nerve
terminal, resulting in reduction in the release of
quanta of acetylcholine.

This disease is commonly associated with

carcinoma. So, it is also called carcinomatous
myopathy. This disease is characterized by several
features of myasthenia gravis. In addition, the
patients have blurred vision and dry mouth.
 Muscle Dysfunction-continued
5. McArdle disease: This is a glycogen storage
disease (accumulation of glycogen in muscles)
due to the mutation of genes involving the
muscle glycogen phosphorylase, necessary for
the breakdown of glycogen in muscles. Muscular
pain and stiffness are the common features of
this disease.
 Muscle Dysfunction-continued
6. MITOCHONDRIAL MYOPATHY
Mitochondrial myopathy is an inherited disease due to
the defects in the mitochondria (which provide critical
source of energy) of muscle fibers.

7. NEMALINE MYOPATHY
Nemaline myopathy is a congenital myopathy
characterized by microscopic changes and formation of
small rod-like structures in the muscle fibers. It is also
called nemaline-rod myopathy. The features are delayed
development of motor activities and weakness of
muscles