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NERVE AND MUSCLE PHYSIOLOGY

DR. VIVEK V. NALGIRKAR

Professor, Physiology

• Section 1: Neuron – The structural & functional unit of nervous system

• Section 2: Classification of neurons, classification of nerves and nerve fibers;
Wallerian degeneration
• Section 3: Nerve biophysics – Resting membrane potential (RMP), Action potential
(AP); Phases, ionic basis, properties, and propagation of AP.
• Section 4: Muscle Physiology – Introduction, Neuromuscular junction, Excitation-
contraction coupling
• Section 5: Sarcomere – Structure, changes during muscle contraction
• Section 6: Factors influencing strength of contraction of a muscle
• Section 7: Smooth muscle; Cardiac muscle

This chapter broadly has two parts ~ 1. Nerve and 2. Muscle.

Neuron and nerves are related to the nervous system. However, somatic nerves
send signals for muscle contraction; autonomic nerves control the cardiac &
smooth muscle. Hence, the nerve structure and biophysics is discussed in the
present chapter which mainly deals with muscle physiology.

Muscle Physiology deals extensively with skeletal muscle. Also, there is a section
on smooth muscle. Cardiac muscle is dealt with in great detail in the
cardiovascular system (CVS).

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INTRODUCTION:

A terminally differentiated tissue is the one which is no more in the cell growth
cycle.

- The nervous tissue is a highly specialized tissue of ectodermal origin. It is a

terminally differentiated tissue, and is incapable of further redifferentiation.
If such a tissue is injured or damaged, there can not be formation of new cells
to replace the damaged ones. Hence, the nature has provided a protective
architecture that guards the central nervous system.
- The brain and the spinal cord are confined within the rigid cranial cavity and
the vertebral canal respectively. Thus, they are protected from external
environment but at the same time communicate with it through peripheral
nerves. In addition, the meningeal coverings (dura, arachnoid, pia mater)
invest the brain and the spinal cord.
- Nerves also communicate with and regulate the functioning of the various
organ systems within the body.

Characteristic features:

➢ Macroscopically, the nervous tissue consists of grey and white matters.

➢ Microscopically, the grey matter consists of nerve cells of varying shapes
and sizes; each nerve cell consists of a cell body with branching processes.
Absence of centrosome and the presence of Nissl’s granules and
neurofibrils in mature nerve cells are special features of nerve cells.

Grey and white matters-

In the brain, grey matter is at the periphery and white matter is toward the
center. In the spinal cord, grey matter is at the center and white matter at
the periphery. WHY?
The nervous system develops from the neural plate and the neural
tube. During the early (embryonic) days, the nerve cells are found to be
scattered at random; the cells and their dendrons and axons mingle together
in a mesh. Subsequently, the cell bodies are gathered in groups (called
nuclei) and their fibers run into bundles (called tracts). This organization is

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 governed by the principle of NEUROBIOTAXIS (nerve-living attraction). The
principle of neurobiotaxis postulates that the nerve cells migrate towards the
source of stimulation. Thus, in the spinal cord, the cells are concentrated
towards the central canal or centrally. These centrally migrated cells are
richly supplied with capillary blood vessels, and this mixture of cells and blood
vessels gives out a grey appearance on a cross-section and is called the grey
matter. The long processes of the neurons, which run a long way from the
parent cell bodies, acquire a fatty sheath, the myelin sheath, around them
which has a high refractive index. It is due to this myelin sheath, the mass of
fibers gives a white appearance and hence it is called white matter.

Functional divisions of the nervous system:

- Nervous system is a regulatory system that sends signals to various organ

systems involved in homeostasis. It also communicates with the external
environment.
- The functional divisions: (1) Central nervous system [CNS], (2) Peripheral
nervous system [PNS], and (3) Autonomic nervous system [ANS].
- Central nervous system is made up of the brain and the spinal cord.
- Peripheral nerves collect the sensory signals arising from the environment
and carry them to the spinal cord. Motor peripheral nerves innervate the
musculature.

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 Section 1

Neuron: The basic structural unit

Learning objectives:

- Learning the structure of a neuron is essential in order to understand how

impulses are transmitted in the nervous system.
- This section describes the structure of a neuron, and injury and
subsequent repair of a nerve.

NEURON:

- It is the basic structural and functional unit of the nervous system

- A nerve cell is made up of a cell body known as the cyton (soma or
perikaryon), and short and long processes known as the dendron and the
axon respectively. The component unit of a nervous pathway formed by a
single nerve cell with its processes is called a NEURON.
- The nerve cell receives impulses through its dendron and transmits the same
through its axon to other cells. The axon of one cell ends on a dendrite or cell
body of another neuron; this junctional region between the two neurons is
called synapse.)

Nerve nucleus: Any localized collection of cells within the central nervous system
is called the nucleus.

Nerve ganglion: Any collection of nerve cells in the course of a peripheral nerve is
known as the ganglion. It acts as a relay station in a nervous pathway.

Structure of a neuron-

A nerve cell with its appendages or extensions forms a neuron.

It consists of a nerve cell body (soma or perikaryon), many small extensions all
around it (the dendrites), and a long process at one side (the axon/axis

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cylinder/nerve fiber). The nutrition of the axon and the preservation of its structure
depend on its intact connection with its cell body.

[Fig: It shows the nerve cell and its extensions. The dendrites are the small extensions all
around the nerve cell body. One long extension at one end is the axon. The axon or the axis
cylinder is covered with myelin sheath. Myelin sheath is broken at regular distances where the
axonal membrane is exposed; these points are called nodes of Ranvier. Axon hillock or initial
segment is the first point where an AP is generated and then transmitted down the axon. Refer
to the section of action potential for further details. Also note: When a neuron passes the
impulse to another neuron, axon of the first neuron ends on the dendrite of the next neuron;
this is called excitatory synapse. When a neuron is making an inhibitory connection with
another neuron, then the axon of the first neuron ends on the cell soma of the next neuron.]

➢ The cytoplasm of a nerve cell contains Nissl granules, mitochondria, Golgi

apparatus, and fine, long filaments of neurofibrillae.
• Nissl granules: (also called Nissl bodies, or tigroid substance – due to
tiger-like dark spot appearance) These basophil masses are composed
of thin, membrane-bound cavities. The granules are composed of
ribose nucleoproteins (RNP). In conditions of fatigue, injury to the

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 nerve, or action of certain poisons, the Nissl granules disintegrate into
a fine dust and eventually disappear (“chromatolysis”).
• Neurofibrllae: The fibrillar, thread-like structures in the cytoplasm of
nerve cells.
• Dendrites: They branch out extensively as they leave the nerve cell
body. They are the receptor zones for a nerve; receive signals from
another nerve and send it to the axon of the nerve.
• The axon (axis cylinder/nerve fiber): Arises from one end of the nerve
cell body. It arises from the part of the nerve cell called axon hillock
(the initial segment of the axon).

Note: The axon is the nerve fiber. It carries impulse over long distances.

(i) Majority of nerve fibers have a covering of a myelin sheath. Such cells are
called the myelinated nerve fibers. Myelin sheath is formed from
Schwann cells. The neurilemma (sheath of Schwann) is the outermost cell
membrane of the Schwann cell.
(ii) Surrounding the neurilemma of nerve fibers is a thin layer or covering
called the endoneurium.
(iii) The nerve fibers are arranged in bundles or fascicles. These bundles are
enclosed in a connective tissue capsule called the perineurium.
(iv) A number of bundles/fascicles are bound together by connective tissue
covering called the epineurium.

Note: A nerve fiber is a single axon. Often, the bundles of axons run together. A
bundle of nerve fibers may be differentially called as tract, fasciculus, funiculus, or,
lemniscus.

• Myelinated or medullated nerves:

Majority of the peripheral nerves and those in the CNS are enveloped by the
myelin sheath, and hence are called myelinated or medullated nerves.
Myelin sheath has high refractive index, and is white in color. (Nerves appear
white due to the myelin sheath.)

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Myelin sheath is not a continuous covering. At regular intervals, the nerve
fiber is devoid of this cover. These gaps are called the nodes of Ranvier. The
average internodal distance is about 1 mm.
➢ Myelination of the peripheral nerves is by Schwann cells; myelination in
the CNS is by oligodendrocyte.
➢ One Schwann cell myelinates the distance between two nodes of Ranvier.
➢ Myelin is lipid-rich; it is composed of protein and several lipids, such as
cholesterol, lecithin, and cerebrosides (sphingomyelin).
➢ Function of myelin sheath: due to the presence of lipids, the myelin
sheath acts as an insulator and prevents flow of all ions across the nerve
fiber membrane.
➢ Myelinogenesis: Myelin sheath is formed by the double-layered infolding
of Schwann cell membrane which spirally wraps up the axon in a few
concentric layers.
➢ Myelinogenesis in the CNS: The nerve fiber tracts/pathways achieve fully
functional status only when their myelination is complete.
▪ The sensory tracts are myelinated first; the dorsal columns of spinal
cord are myelinated between 4th and 5th month of the intrauterine
life.
▪ The spinocerebellar tracts are myelinated subsequently.
▪ Myelination of the motor tracts begins at the 2nd month of the
infant life (i.e. starts after birth). Pyramidal tract myelination is
completed between 18 months and 2 years of age. (A child can
attempt to walk only when pyramidal tract begins to function.)

Video link ~ The lipid-rich myelin and

“nitrogen narcosis”

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 Section 2

Classification of neurons, nerves, and nerve fibers

Classification of neurons-

Functionally, the neurons may be classified as:

a) Motor or efferent neurons- it may further divided into upper motor neuron
(UMN) and lower motor neuron (LMN).
b) Sensory or afferent neurons- carry impulses from periphery to center
c) Interneurons (or internuncial neurons or intercalated neurons)- small
neurons that connect afferent and efferent neurons

Structurally, depending on the length of their axons:

a. Golgi type I – long axons that establish connection with remotely placed
organs or cells
b. Golgi type II – small cells with short axons

According to the poles:

a) Multipolar neurons – axon arises from one end and dendrites arise from
all other sides of the nerve cells. They are widely distributed in the
cerebral cortex, cerebellum, and the spinal cord.
b) Bipolar neurons – the cells are in fusiform in shape and have two poles;
axon arises from one end and dendrites from the opposite end. They are
found in the ganglion of VIII cranial nerve, retina, and olfactory nasal
epithelium.
Pseudounipolar neuron ~ This type has only one extension from its cell
body. The extension is a single axon that splits into two branches. E.g.,
neuron whose cell body lies in dorsal root ganglion (DRG).
c) Unipolar neurons – have only one pole; dendrites and axon arise from
same side. This type is found only in fetal brain; in adults, only the sensory
nucleus of the V cranial nerve has unipolar neurons

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 d) Anaxonal neurons – Have no axon; not required to send impulses over a
distance. E.g., amacrine cell in retina, post-ganglionic parasympathetic
nerve

Multipolar Cerebral cortex,

cerebellum,
(Most common)

Bipolar Retina, olfactory neuron

Pseudounipolar Dorsal root ganglion

(DRG)

Unipolar Mostly in fetal brain;

sensory nucleus of V N (in
adults)

Anaxonal Amacrine cell in retina,

post-ganglionic
parasympathetic

Video link ~ Anaxonal neuron; a nerve cell

but no nerve fiber?

Classification of nerves:

(I) According to the origin/location of the fibers-

a. Cranial nerves: there are 12 pairs of cranial nerves that arise from the
brain
b. Spinal nerves: there are 31 pairs of spinal nerves that arise from the
spinal cord
(II) According to the function that they perform-

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 a. Sensory nerves: they carry sensory impulses from the periphery
toward the spinal cord/brain. (afferent nerves – starting from
periphery and going to the center)
b. Motor nerves: they carry motor impulses brain/spinal cord to the
effector organ. (efferent nerves – starting from center and going to the
periphery)
c. Mixed nerves: sensory fibers & motor fibers
(III) According to the myelination status-
a. Myelinated or medullated nerves: they have myelin sheath covering
b. Non-myelinated or non-medullated nerves: they do not have myelin
sheath.
(IV) According to the type of function they perform-
a. Somatic nerves: they perform voluntary (conscious) function, such as
skeletal muscle contraction
b. Autonomic nerves: they perform involuntary function, such as control
of heart rate.
Autonomic nerves are of two types – sympathetic nerves and
parasympathetic nerves
➢ Ganglion is a relay station for the two nerves: the nerve that ends in a
ganglion is “preganglionic”; the nerve that starts from there is
“postganglionic”.
➢ According to the neurotransmitter released, the nerves may also be
classified as: (i) adrenergic – release noradrenaline and adrenaline; (ii)
cholinergic – release acetyl choline; the other nerves are dopaminergic,
serotonergic, GABAergic, etc.

~ Classification of nerve fibers:

The classification is based on the diameter of the fiber and the conduction
velocity of the impulse transmitted through the fiber.

[Erlanger and Gasser classification]

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 Fiber type Function Fiber diameter Conduction
(mm) velocity (m/s)
A
 Proprioception; 12-20 70-120
somatic motor
 Touch, pressure, 5-12 30-70
motor
 Motor to muscle 3-6 15-30
spindles
 Fast pain, cold, 2-5 12-30
touch
B Preganglionic <3 3-15
autonomic
C
somatic Slow pain, 0.4-1.2 0.5-2
temperature
autonomic Postganglionic 0.3-1.3 0.7-2.3
sympathetic

{ is the thickest nerve fiber with fastest conduction velocity; proprioceptive
impulses into the CNS and motor impulses to skeletal muscles are transmitted by
these fibers. A    B, and C are in descending order, in terms of thickness
and conduction velocity.}

Numerical classification:

Only the sensory fibers are taken out from the above classification, and are grouped
under numerical classification ~

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 Type Erlanger & Gasser type Function

Ia A Primary afferents arising

from muscle spindle

Ib A Afferents from Golgi

tendon organ

II A Secondary afferents from

muscle spindle

III A Pain- & cold-carrying

fibers

IV C Pain- & warmth-carrying

fibers

[Note: Type Ia, Ib, and II carry proprioception. They will be mentioned again in CNS chapter, in
the context of proprioceptors – muscle spindle & Golgi tendon organ.]

Degeneration and regeneration of nerves:

• Nerves in the CNS, if injured and degenerated, do not regenerate. Repair is

not possible for a damaged CNS nerve. However, a peripheral nerve, if
injured or damaged, does show regeneration and repair.

Myelin formation of the nerves in CNS is achieved by the oligodendrocytes.

One oligodendrocyte is associated with myelination of almost 20 neurons.

Myelin formation of the peripheral nerves is achieved by the Schwann cells.

One Schwann cell myelinates only a small portion of a neuron between two
adjacent nodes of Ranvier. When a peripheral nerve is injured, an intact
neurilemma sheath is left behind. It does provide a definitive path for an
injured nerve fiber to regrow. Hence, repair is possible in the case of a
peripheral nerve.

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- Injury to a peripheral nerve, and its consequent degeneration, may occur if a nerve
is sectioned, crushed, or if its blood supply is blocked.

➢ Degrees of severity of an injury to a nerve: [Sunderland’s classification]

1. First degree injury: most common; caused by pressure that leads to occlusion
of the blood flow, or direct effect of pressure on the nerve. The axon is not
destroyed; it only loses its function for some time.

2. Second degree injury: Severe and/or prolonged pressure leads to

degeneration of the nerve.

3. Third degree injury: Endoneurial tube is disrupted.

4. Fourth degree injury: Nerve fascicles are disorganized.

5. Fifth degree injury: Nerve trunk is severed.

[Fig: It shows a nerve trunk, with 3 fascicles (bundles) of nerve fibers. 1st and 2nd degree injury
is caused by the pressure/compression of the nerve trunk. 3 rd degree is when a single axon is
disrupted. 4th degree injury refers to disruption of a bundle. 5th degree injury is when the entire
nerve trunk is transected.]

With a 5th degree injury, following degenerative changes occur in the nerve – (The
changes are called Wallerian degeneration; described by Augustus Waller.)

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➢ Wallerian degeneration:

(When a nerve is sectioned, there will be two parts of its axon:- the part
toward the nerve cell body is called the proximal stump, and the other part
away from the nerve cell body is called the distal stump.)

• Changes in the nerve proximal to the injury: (from the site of injury toward
the cell body of the neuron, there is degeneration up to the nearest node
of Ranvier.)

- Chromatolysis: (begins within 48 hours) –

Nissl substance begins to disintegrate into a fine dust.

Cell body imbibes water and swells up.

Nucleus is pushed to the cell margin.

The changes are completed within 2 weeks.

• Changes distal to the site of injury:

- Up to 3 days, the distal stump can conduct an impulse. After that, it does
not function.

- The axis cylinder breaks up. The distal stump and its associated synaptic
endings disintegrate by 6th day.

- Myelin sheath also disintegrates. Physical destruction of myelin occurs by

8-10 days; chemical destruction of myelin takes about 8-32 days.

• Regeneration of the nerve: (Intact neurilemma sheath is necessary for

regeneration)

- Repair of the nerve begins by about 20 days after the injury and is complete
by 80 days.

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 - Schwann cell proliferation: Schwann cells in the distal stump proliferate
and grow in all directions from the cut end. Eventually, the gap between
the cut ends is bridged by the Schwann cells.

- Sprouting: The proximal stump develops sprouts. The sprouts get

elongated and grow along the strands of the Schwann cells, into the
endoneurial tubes. It takes about 2-3 weeks.

- Myelin sheath begins to develop in about 15 days and follows the course of
the growing fibrils. Myelination is completed within a year.

- Increase in fibre diameter takes place very slowly. Regenerated fibres may
attain a diameter 80% of the original (or even less).

Video link ~
Wallerian

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 Section 3

NERVE BIOPHYSICS:

THE BIOELECTRIC POTENTIALS IN NERVES

RESTING MEMBRANE POTENTIAL (RMP) AND ACTION POTENTIAL (AP)

Learning objectives:

- A nerve sends signals to another nerve or to a muscle. These signals are in

an electrical format. In diseases like multiple sclerosis, the signaling is
interrupted. It is important to understand how these electrical signals are
generated and transmitted, and to learn their properties.
- This section narrates the origin and development of the membrane
potential when a nerve is resting. It also describes generation of an
excitatory signal, called action potential (AP), and its propagation through
a nerve.
- Functioning of various organ systems can be assessed by recording of
electric potentials from their respective cells, viz., ECG for heart, EMG for
nerve & muscle, EEG for brain. Understanding of these investigations will
become easier after learning this section.

Introduction:
An electrical potential (voltage) difference exists across the membranes of
all cells. This potential is called membrane potential. The membrane potential is
negative; i.e. inside of all cells is negative (voltage) compared to the exterior. This
negative potential on the inside of cell membrane is of different value for different
cell types in the body.
➢ Red cell, epithelial cell ~ (less negative) – 8 to – 20 mV
➢ Smooth muscle cell ~ – 35 to – 45 mV
➢ SA nodal cell ~ – 55 to – 65 mV
➢ Nerve ~ – 70 mV
➢ Skeletal muscle, Purkinje fiber ~ – 90 mV

Concept of “excitable” cells:

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 For the cells like red cells or epithelial cells (non-excitable cells), this
potential remains unchanged.
There are cells in the body for which the negative membrane potential
briefly turns positive. This happens whenever these tissues are
stimulated. It is called membrane excitation. (The potential immediately
recovers to its original negative value.)

(i) When they are not stimulated, they are said to be resting. Hence,
their negative membrane potential then is called “RESTING
membrane potential”.
(ii) When they are stimulated, their membrane potential turns
positive. This is called their excitation, and the potential is called
“ACTION potential” (AP).

Thus, nerve and muscle are said to be “excitable” tissues. They exhibit electrical
excitation of their cells.

(Some other cells are also excitable ~ receptors in CNS, pancreatic beta cells, etc.
However, the present chapter deals with nerve & muscle excitation.)

Purpose of membrane excitation:

A nerve fiber has to send ‘signals’ over long distances. The signaling by the nerves
is in the form of this membrane excitation or AP.

Muscles have to contract, and for that, they have to receive a signal. The signal for
muscle contraction is in the form membrane excitation. That is, a signal will travel
through a nerve, it will enter a muscle, muscle membrane will excite, and this will
result in muscle contaction.

Note: The Nomenclature

Excitation at a single point is called action potential.

When action potential travels like a signal, it is called impulse.

Recording the resting potentials and action potential:

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 ➢ Intracellular recordings of membrane potentials are made with glass
microelectrodes.
➢ Extracellular recordings usually are made with metal electrodes that are
placed on or near the nerve or muscle.
➢ Extracellular recordings are useful in clinical situations when the electrical
activity of excitable tissues must be monitored. For example,
electroencephalograms (EEGs) are used to aid in the diagnosis of brain
disease, electrocardiograms (ECGs) are used to detect damage to the
heart, and electromyograms (EMGs) are used to aid in the diagnosis of
neuropathies.

Two points may be noted here ~ (1) The membrane potentials (RMP & AP) are the
potentials on the inside aspect of the membrane. (2) The values for membrane
potentials are considered with respect to the ECF which is taken as 0 mV.

Video link ~ Transmembrane electrical

gradient; exception of hair cell

Resting membrane potential (RMP) –

➢ Definition – Under resting conditions, a potential difference exists across the

membranes of the nerve and muscle cells. This potential, caused by excess
negative charges on the inside of these membranes, is called the Resting
Membrane Potential (RMP).

The resting membrane potential of nerve: – 70 mV

The resting membrane potential of skeletal muscle: – 90 mV

Origin and development of RMP:

- Two processes, occurring simultaneously, are responsible for development

of RMP:
(i) Diffusion of the Na+, K+, and Cl-
(ii) Na+ - K+ pump

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(i) Diffusion of ions; concept of “diffusion potential” or equilibrium
potential:
[Recall the concept of equilibrium. An ion is said to have reached
equilibrium when there is no net movement of the ion. Also remember that
the diffusion of ions occurs due to concentration gradient as well as
electrical gradient.]
- Let us consider a typical cell, with concentrations of Na+, K+, and Cl- inside
and outside of it.
- Let us take the example of Na+, to understand the concept of equilibrium
potential. (Also refer to the figure below.) Note: While we consider
equilibrium potential for an individual ion, it is assumed that only this ion is
allowed to diffuse, whereas all the other ions are not moving.
- Na+ has concentrations of 141 mEq/L and 14 mEq/L in ECF and ICF,
respectively. This is the starting point. Now, by concentration gradient, Na +
starts diffusing from outside to inside of the cell.
- Na+ brings positive charges into the cell; these positive charges now line up
just on the inside of the membrane.
- Thus, the movement of Na+ will cause two things ~ (1) The concentration
gradient for Na+ (outside to inside) will decrease, and (2) an electrical
gradient will get created across the membrane, with more positive charges
lined up inside the membrane, as compared to just outside.
- Narrowing of the concentration gradient (outside to inside) and creation and
widening of the electrical gradient (inside to outside) will lead to a stage
when both the forces will become equal.
- At this stage, due to the equal but opposing forces, there will be no net
movement of Na+. Na+ is said to have reached equilibrium.
- What will be the charge on the inside of the membrane at this stage? This
charge or potential is called equilibrium potential for Na+.

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[Fig: Na+ reaching equilibrium. Green arrow = concentration gradient; red arrow
= electrical gradient. (1) Na+ starts moving down its concentration gradient, from
outside to inside. It brings into the cell the positive charges which then line up on
the inner aspect of the membrane. (2) An electrical gradient is now created with
more positive charges on the inside of the membrane. This causes Na+ to diffuse
out. (3) Eventually, the concentration gradient and electrical gradient are equal
(but in opposite directions), as shown by red & green arrows. No net movement
of Na+; it has reached equilibrium.]

Equilibrium potential for an ion is that membrane potential at which there is no

net movement of the ion. It is calculated by using Nernst equation.

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 The Nernst equation: (calculation of diffusion potential or equilibrium
potential for an ion)

Conc. outside
EMF (millivolts) = ± 61 X log.
Conc. inside

EMF is electro-motive force.

➢ Concentrations of Na+ on the outside and inside of the membrane are 141
mEq/L and 14 mEq/L respectively. The ratio [outside/inside] would be
[141/14 ~] 10. Log of 10 = 1. 61 X 1 = 61 mV. Na+ is a cation and its initial
movement was into the cell, causing positive charges to line up on the
inside. So, eventually when equilibrium is reached, charge on the
membrane will be +ve (plus). EP for Na+ is +61 mV.
➢ Concentrations of potassium inside and outside are 140 & 4 meq/L
respectively. Putting these in the Nernst equation gives the value of –
96mV.
➢ Equilibrium potential for Cl-, by Nernst equation, is – 89 mV.

Video link ~ (1) Which sign do we take in Nernst equation, for

respective ions? (2)Equiliubrium is a
hypothetical concept.

➢ Note: If only Na+ moves and reaches equilibrium, charge on the

membrane will be +61 mV. If only K+ moves and reaches equilibrium,
charge on the membrane will be – 96 mV. Now consider both Na+ & K+
are diffusing simultaneously, and ultimately the actual RMP established is
– 90 mV, which is very close to the diffusion potential for K+. It can be
concluded that it is the diffusion of K+ which contributes maximally to
the development of the RMP. In other words, potassium drags the RMP
toward its own equilibrium potential. What is the reason for this?

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 REASON:- In the resting state, the membrane permeability for K+ is about
almost 50 times as great as it is for Na+. So, if both Na+ and K+ are allowed
to move simultaneously, K+ movement will be much much more, and Na+
movement will contribute very less to the development of RMP.
➢ Cl- equilibrium potential is – 89 mV, which is very close to the RMP. So, Cl-
hardly moves (remains in equilibrium) when the cell is at RMP.
EXPLANATION: Equilibrium potential for an ion is that membrane potential
at which the ion will be in equilibrium. So, if a cell is at RMP ( - 90 mV) which
is almost the same as EP for Cl- (- 89 mV), Cl- will remain in equilibrium.

Video link ~ Membrane potential, EPs of ions, and their relative

movements (If the membrane potential is close to the EP for an ion, the
ion movement will be very little).

➢ When all the ions (Na+, K+, and Cl-) move simultaneously, their respective
movements will be dictated by two factors: (a) their respective concentration
gradients and (b) relative permeability of the membrane for these ions.
➢ The charge produced on the membrane, by the diffusion of these ions, can
be calculated by Hodgkin & Huxley equation: (also called Goldman’s
constant field equation) (It is an expanded version of the Nernst equation in
which the concentrations {C} of the ions are multiplied by their membrane
permeabilities {P}.)

[CNa+(o) X PNa+]+ [CK+(i) X PK+]+ [CCl-(o) X PCl-]

EMF (mV) = ± 61 X log.
[CNa+(i) X PNa+]+ [CK+(o) X PK+] + [CCl-(i) X PCl-]
Where, (o) and (i) are concentrations of the ions on the outside and inside of the
membrane, respectively; P represents the permeability of the membrane for the
ion. Also note ~ for respective ions, their higher concentrations are taken in the
numerator and lower concentrations taken in the denominator.
With this equation, the potential created on the membrane, by the diffusion of Na+,
K+, and Cl-, comes out to be – 86 mV.

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(ii) Contribution of the Na+ - K+ pump: ( - 4 mV)
Since the pump is causing 3 Na+ ions to go out of cell but only 2 K+ ions
come in, there is a deficit of one positive charge on the inside. Thus, as
the pump continues its activity, it causes a deficit of positive charges on
the inside of cell, causing relatively excess negative charges. It amounts
to – 4 mV being contributed to the RMP.
❖ In summary, – 90 mV is the RMP of skeletal muscle cell. Of this, – 86 mV is
contributed by diffusion of Na+, K+, and Cl- (greatest contributor is K+
diffusion), and – 4 mV is by Na+/K+-pump (that is, by active transport).

Skeletal muscle Nerve

- RMP – 90 mV – 70 mV

- EP for Na+ + 61 mV + 60 mV

- EP for K+ – 96 mV – 90 mV

- EP for Cl- – 89 mV – 70 mV

VIDEO LINK ~ Why are the values different

for muscle and nerve?

• Membrane excitation and impulse transmission:

Nerve signals are transmitted in the form of electrical excitations.
There are two types of signal transmission ~ (1) Electrotonic conduction, and
(2) Action potential (AP) propagation.

- 24 -
 - In electrotonic conduction, positive charges enter from one point on the
nerve, and then these charges flow passively over some distance. There will
be leakage of charges across the membrane as they flow inside the nerve;
hence, this type of signal will die out after having travelled over a certain
distance. From dendrite to axon hillock, the signal travels electrotonically.
- In AP propagation, a point on the nerve will excite by the entry of positive
charges. Then, every next point on the nerve will have the same changes of
excitation (by entry of positive charges).

[Fig: In electrotonic conduction, Na+ channel opens at one point; the positive
charges enter through the point and then spread passively over a certain
distance. In AP propagation (unmyelinated nerve), Na+ carries positive charges
through a point, resulting in membrane excitation at the point. Same events occur
at every next point of the nerve.]

- 25 -
 • ACTION POTENTIAL (AP):
Definition:

Action potential in a nerve may be defined as: “excitation of the membrane,

with transient reversal of membrane potential, which travels through the
nerve in a self-propagated and non-decremental manner.”

The events of an action potential, developed at a point on the nerve, can be

recorded by cathode ray oscilloscope (CRO).

{Electrodes are applied to a nerve, and then are connected to an amplifier. The
electrodes pick up the electrical events in the nerve. The electrical events are
transferred to the metal plates in the CRO. A cathode in the CRO emits electrons
that pass through the metal plates and those electrons strike the face of the glass
tube of CRO. The deflections of the electron beam give a graphic representation of
the potential changes in the nerve.}

The graphic representation of an action potential, recorded from a point on the

nerve, shows following phases:

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[Fig: It shows a graphic depiction of the events occurring during action potential
development at one point of a nerve. The events are described in the text below.]

(i) Resting stage:

The nerve fibre membrane has a resting membrane potential of
The membrane is said to be “polarized” because of the – 70 mV negative
potential on the inside of the membrane. (When this resting ‘polarity’ is
“disturbed” and interior of the membrane becomes positive, it is called
“Depolarization”; and then the polarity is “restored”, it is called
“Repolarization”.)
(ii) Depolarization: {sodium entry into the nerve}
The membrane becomes permeable to sodium ions, allowing tremendous
numbers of positively charged sodium ions to flow to the interior of the

- 27 -
 axon. The inside of the axon becomes positive. This is called
“DEPOLARIZATION”.
(iii) Repolarization: {potassium efflux out of the nerve}
The sodium channels close, thus inside potential stops becoming any
more positive. Potassium channels begin to open more and more now.
Potassium ions leave the nerve, thus causing positive charges to go out.
This causes the interior of the membrane to again become negative. It is
called “REPOLARIZATION”.

{Note that: sodium and potassium are moving along their concentration gradients;
higher-to-lower concentration.}

Details of the phases and their ionic basis:

➢ When the stimulus is applied to the nerve, there is a brief irregular

deflection of the baseline, called stimulus artifact. This artifact is due to
current leakage from the stimulating electrodes to the recording
electrodes. It is not the part of membrane excitation, but it is of value
because it marks the time at which stimulus was applied.
➢ The stimulus artifact is followed by an isopotential interval called latent
period. It corresponds to the time taken by the impulse to travel from
stimulating electrode to the recording electrode. (If the duration of the
latent period and the distance between the electrodes are known, the
speed of conduction in the axon can be calculated - distance ÷ time)
➢ As the depolarization begins, membrane potential gradually decreases to
a less negative value. After an initial 15 mV, as the potential reaches a
value of – 55 mV, suddenly a massive influx of sodium ions occurs. This
level is called the firing level or threshold. Note the importance of this
point called threshold. If the stimulus is weak, and the membrane
depolarization does not reach this threshold level, AP will not be
completed (membrane will not excite). And, with adequate stimulus
strength, once the threshold potential is reached, AP becomesinevitable
(it will definitely happen).

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 ➢ Reaching of threshold potential:- The positive feedback cycle of Na+ entry

[Fig: Positive feedback cycle of Na+ channel opening and Na+ influx. Read the text
below.]

As the stimulus causes some Na+ channels to open initially, Na+ enters the nerve.
Membrane potential drops to a less negative value. This change of voltage causes
some more sodium channels to open, causing some more Na+ to enter, which
causes a further depolarization of the membrane. This causes some more sodium
channels to open.
The positive feedback cycle of Na+ channel opening and more & more
depolarization eventually causes the membrane potential to reach the threshold
value.

- 29 -
 ➢ At threshold: A critical number of Na+ channels is open now. There is a
massive influx of positive charges (Na+), almost in an explosive fashion,
causing the potential to rise very rapidly to zero and become positive. This
part of the graph is called upstroke and overshoot. (The graph shoots past
zero; hence the term “overshoot”.) The potential of the membrane
reaches approximately + 35 mV.
Na+ channels are now inactivated, so further entry of Na+ will not occur. The
membrane potential has now reached about + 35 mV.
➢ As the sodium influx has stopped, and potassium ions (positive charges)
start leaving the fiber in large numbers, the membrane potential becomes
negative again (repolarization). The sharp rise and rapid fall of the
potential in the graph are called the spike potential.
➢ Toward the end of repolarization, the fall of potential is slower. This is
called after-depolarization.
➢ After reaching the previous resting potential, the graph overshoots
slightly in a more negative direction. This is called after-hyperpolarization
or simply, hyperpolarization.

Gating behaviour of the channels-

➢ Na+ channels:

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[Fig: It shows the gates and the gating behaviour of voltage-gated Na+ channels.
Only when both ‘m’ and ‘h’ gates are open, Na+ influx would be possible.]

Sodium channel has “m gate” that covers the extracellular side of the channel. It is
the “activation” gate for the channel.

It has “h gate” that covers the intracellular side of the channel. It is the
“inactivation” gate for the channel. Na+ can diffuse through the channel when both
gates are open.

Voltage dependence:
The sodium channels are said to be “voltage-gated”; that is, the gates of
the channel open or close according to the voltage changes of the
membrane.
(i) In the resting state of the nerve:

- 31 -
 The activation gates (“m” gates) are in a closed state. The inactivation
gates are open. This is the “resting” state of the channels.
(ii) Depolarization:- activation gates are opened :
When a stimulus is applied, the activation gates (“m” gates) open.
Since both “m” and “h” gates are now open, Na+ influx will occur.
(iii) Inactivation gates closed: Na+ channels inactivated (Refractory
period)
At the threshold, there is a sudden and massive influx of Na+. It
causes the membrane potential to shoot up instantly to + 35 mV.
As this is happening, the inactivation gates begin to close. The
membrane potential has reached a value of about + 35 mV. Na+
channels are now in an inactivated state. They will remain in this
inactivated state until the membrane repolarises to about – 40 mV.
Once the membrane has repolarised to this potential, the
inactivation gates begin to open and the Na+ channels again go
into the “resting” state. As long as the Na+ channels are in the
inactivated state, the nerve can not be excited once again. Then,
when the Na+ channels recover and again go into “resting” state,
the nerve can be excited again.

Video link ~ Na+ channel gates. Why is the “m” gate on the
external aspect of the
membrane, and “h” gate on the intracellular aspect?

- 32 -
 Resting state
Inactivated
(at RMP):- “m”
state: “h” gates
gates are closed;
are closed.
“h” gates are open

Activated
state: “m” gates
open; Na+ influx
and Depolarization
occurs

➢ Behavior of potassium channels:

The potassium channel is regulated by a single gate – the “n gate”. It is
located on the extracellular side of the channel. When the “n gate” (the
activation gate) is open, the potassium flows out of the cell. Potassium
channels do not have inactivation gate. The same “n” gate opens and
closes on activation and inactivation of the channel.
Time-dependence: a property of K+ channels

- 33 -
 ➢ As the membrane begins to depolarize, and sodium starts flowing in,
potassium channels also begin to open but very very slowly. Thus,
potassium (positive charges) leaving the nerve is in a miniscule amount,
and has almost no effect because sodium is coming into the nerve in
relatively large numbers. This will cause depolarization.
➢ However, as the time has lapsed and membrane is completely
depolarized, now the potassium channels begin to open in large numbers.
At this time and at this potential, sodium entry has already stopped. Now,
as the potassium starts leaving the nerve in large numbers (positive
charges leaking out), inside of the fiber again becomes negative and
reaches its original resting potential.
(Note: K+ channels also show “voltage-dependence”. At the negative
voltage of the RMP, they open very slowly. Their opening gains momentum
when the membrane is depolarised (positive potential).

Hyperpolarization:

{It should be noted that potassium channels are slow to open and slow to
close.}

As the potassium channels are slow to close, they allow excess potassium (that is,
positive charges) to leave the nerve fiber during repolarization. This creates excess
negativity on the inside of the fiber, at the end of repolarization. This state is called
“hyperpolarization”. The potential inside would be more negative that the normal
resting value ( - 80 or – 90 mV, instead of original resting value of – 70 mV).

{Significance of hyperpolarization: It should be recalled that, an AP is fired only if

the membrane potential reaches a certain “threshold” value. Now, if the fiber is
more negative than its normal resting value, sodium channels are in inactive state,
and it is more difficult to cause sodium entry and to reach the threshold value. Since
excitation/depolarization will not occur, the nerve is said to be “inhibited”. Thus, a
hyperpolarized cell means a temporarily inhibited cell.}

~ Properties and related features of an action potential (AP) :

(1) ALL-OR-NONE principle:

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 The action potential (AP) obeys “all-or-none” principle.
If the stimulus is not of adequate strength, the AP will not be fired at all
(“none”). When the stimulus is just adequate, the AP will be fired completely
(from – 70 mV to +35 mV). Now, if the stimulus strength is increased further,
the AP amplitude will not increase (it will remain the same). Because, for just
adequate stimulus itself, there was maximum/full response (“all”). In other
words, if the AP has to occur, it will occur completely, whatever is the
strength of stimulus, above adequate stimulus. And, if the stimulus is not
adequate, AP will not fire at all. THERE IS NO GRADED RESPONSE IN A.P.
[There are no gradations, like small, big, bigger, in an AP.]
Explanation: If the stimulus strength is not adequate, the threshold will not
be reached, and the AP is not completed. If the stimulus strength is
adequate, or any strength more than adequate, it causes the threshold to be
reached and depolarization is completed. Na+ channels will behave in exactly
the same manner for any stimulus which is adequate or more than adequate.
(2) Refractory period:
[Refractoriness means unresponsiveness or does not respond.]
After every stimulus, as the depolarization begins at a point on the nerve,
another stimulus cannot cause that point to excite again immediately. This
time period, immediately after the start of every depolarization, during
which one more depolarization cannot be produced, is called refractory
period. From the start of upstroke of AP till near the end of repolarization,
the nerve is said to be “refractory”; it does not respond to another stimulus.
➢ “Absolute” refractory period: from the start of upstroke until
repolarization is about 1/3rd complete. Even the strongest stimulus will
not be able to excite the tissue for one more time
➢ “Relative” refractory period: from the end of absolute refractory period
till near the end of repolarization. A stronger than normal stimulus may
produce another AP.

Reason for the refractory period: From the resting state, the Na+ channels
are “activated”, and the Na+ influx causes depolarization. One more stimulus
cannot cause the channels to be “activated” again. Then, the channels go

- 35 -
 into “inactivated” state. In this state also, another stimulus cannot open
them. Hence this period is absolutely refractory.

Once the fiber has repolarized to – 40 mV, inactivation gates of some sodium
channels begin to open again. Some Na+ channels now recover and go into
“resting” state. If a stronger than normal stimulus is applied, it may open
activation gates and allow sodium entry to occur. This is called relative
refractoriness.

• Significance of the refractory period: It determines the maximum frequency

with which a tissue can be excited.

Long refractory period for a tissue means the tissue cannot be stimulated at high
frequency.

Video link ~
Significance of
refractory period

(3) Accommodation: (Threshold reached, yet AP is not fired.)

If the sodium entry during initial depolarization is very slow, the membrane
will reach the threshold of firing but will not fire the action potential.
Reason: if sodium entry is very slow, then there will be a lot of time lapse
before membrane reaches the threshold. By now, some of the sodium
channels that had opened early, will begin to close. At threshold, a critical
number of sodium channels have to be open, to allow a large influx of
sodium. Also, due to time lapse, potassium channels will begin to open,
potassium (positive charges) starts leaving the fiber. Due to these reasons,
membrane will not be able to attain positive potential.

Video link ~ Threshold reached yet AP not fired..! When can this
happen?

- 36 -
 (4) Action potential is SELF-PROPAGATED and NON-DECREMENTAL:

(a) Self-propagated: When first point on the nerve is stimulated and it

reaches threshold, AP develops at this point. From here on, the AP will
travel (propagate) through the nerve on its own. Whatever be the length
of the nerve, the AP will continue to travel (without stopping) through the
entire length of the nerve fibre. A travelling action potential is called
“impulse”.
(b) Non-decremental:
As an AP travels through a nerve, its amplitude (- 70 mV to + 35 mV) does
not decrease. At every point, the AP develops with the same amplitude.
Whatever be the length of the nerve, even at the last point the AP
develops with the same amplitude as that on the first point.

Video link ~ Properties of AP; just

like a bunch of firecrackers..!

Clinical application:

Influence of other ions on action potential:

➢ Na+: Increase in plasma Na+ will increase the amplitude of AP.
➢ K+: Decrease in plasma K+ will result in hyperpolarization of the nerve.
➢ Ca++: Stability of the Na+ channel gating depends on sufficient
concentration of Ca++ in plasma. In hypocalcemia (low plasma Ca++), Na+
channel gating becomes unstable. With slightest stimulus, Na+ channels
are opened and remain activated. Thus, there will be volley of impulses
sent to muscles. Muscles go into a sustained state of spasm. This is
termed “tetany”.

- 37 -
 Video link ~ Effect of ions on AP; AP obeys all-or-nothing principle in a given set of
conditions.

• Propagation of the action potential through a nerve-

Propagation occurs because the AP generated at one point on the axon acts
as a stimulus for the production of an AP on the adjacent region of the axon.
Thus, AP is conducted through the axon. The propagated AP is called
impulse.
(a) Propagation in unmyelinated axons: the “local circuit”
- Conduction of an AP is a self-propagating process. Once it is generated at
one point, it propagates by itself without any further stimulation. It moves
along the nerve at a constant amplitude and velocity.
- When AP is generated at one point on the nerve, the membrane becomes
positive due to sodium entry at that point. The adjacent point is still resting
(negative). Hence, the sodium that entered from the previous point will flow
to the adjacent (negative) point – (positive-to-negative) “local circuit”
current flow.
- The adjacent resting point will reach the threshold due to the positivecharges
that came in from previous point. As it reaches threshold, it explodesinto an
AP. The sodium now flows in from this point, and will carry positive charges
to the next resting point. The next point too will reach the thresholddue to
these positive charges, and an AP will be fired at this point now.

- 38 -
[Fig: AP propagation in unmyelinated nerve.]

(b) Propagation in myelinated axons:

“SALTATORY CONDUCTION”

[Fig: Saltatory conduction. AP develops at each node of Ranvier, and the positive charges
entering, through the node, travel electrotonically, up to the next node.]

➢ Myelinated nerves have a covering of myelin sheath; this sheath is

deficient at regular intervals where the fiber is exposed. These places are
called nodes of Ranvier.

- 39 -
 ➢ Voltage-gated Na+ channels are highly concentrated in the nodes of
Ranvier. Myelin sheath acts as an insulator, does not allow leakage of
charges across the nerve membrane.
➢ In myelinated nerves, the AP is fired only at a node of Ranvier. The Na+
that enters through this node, carries positive charges in substantial
amounts up to the next node of Ranvier. This is because the overlying
myelin sheath acts as an insulator, so there is no leakage of charges across
the membrane.
➢ Na+ (positive charges) that reach the next node of Ranvier will cause that
node to reach the threshold voltage; AP will now be fired at this node. Na+
that enters from this node will then travel to the next node of Ranvier.Thus,
depolarization occurs only at the nodes of Ranvier. It looks like AP is
jumping a long distance, from node to node. Hence, this propagation is
called “saltatory conduction”. (saltare = leap/jump)

(It may be noted that, the principle of propagation is the same for both myelinated
and unmyelinated nerves. But, in unmyelinated nerves, every adjacent point fires
the AP due to the Na+ entering from previous point; whereas in myelinated nerves,
Na+ is travelling a long distance to cause AP at next node.)

➢ Speed of propagation of an AP:

It is determined by two factors ~ (A) myelination and (B) diameter
of the fiber.
A. Conduction velocity is faster in myelinated nerves as AP events
occur only at a few points (nodes of Ranvier). In unmyelinated
nerves, every adjacent point develops AP; hence, it will take longer
time for the impulse to travel from point A to point B.
B. Larger diameter means less axoplasmic resistance for the flow of
charges during propagation of AP; hence, velocity can be higher.

(i) In myelinated nerves: the conduction velocity is roughly 6 times the

diameter. E.g., A fiber => 20  diameter ~ 120 m/sec velocity
(ii) In unmyelinated nerves: the conduction velocity is proportional to
the square root of the diameter of the fiber.

- 40 -
~ Advantages of the saltatory conduction:

a) Speed of propagation is faster, compared to unmyelinated. This is because,

in unmyelinated nerves, every adjacent point of the nerve fires an AP (which
will take some time); in saltatory conduction: a node is depolarized and then
charges quickly travel a long distance upto the next node, and then only the
next node depolarizes.
b) Energy spent is less for saltatory conduction.

{Now, in APs: Na+ and K+ are moving along their concentration gradients, that is, it
is their diffusion. Diffusion does not require energy. How come then we are saying
that energy consumption is less in saltatory conduction, compared to unmyelinated
nerve propagation? The answer is “recharging”.}

“Recharging”: re-establishing sodium and potassium ionic gradients after each

impulse. It is done by Na+/K+ pump, which spends ATPs.

V
i
d

Video link ~ Membrane excitation and impulse propagation is

travelling of depolarization;
repolarization is “recovery” from excitation

Clinical Application:

➢ Multiple sclerosis:
- It is a demyelinating disease of the nervous system.
- CNS neurons lose their myelin sheath. Since insulation is lost, there is
leakage of charges across the nerve membrane during AP conduction. It
results in conduction blocks.

- 41 -
- Conduction blocks manifest as tingling & numbness, paresthesias, loss of
motor function.

• Compound action potential:

Propagation of action potentials recorded from a nerve trunk is called
“compound action potential”. A nerve trunk has many types of nerve fibers
(out of the  A A A B, and C) hese fibers have different diameters
and different conduction velocities.
A stimulating electrode applies stimulus to the nerve. Recording electrode is
placed at a distance. The APs will travel through all the fibers of the nerve.
They will reach the recording electrode at different times as the fibers are
conducting them at different speeds. Hence, a multi-peaked graph will be
recorded. First curve will be of A fibers, and then in the order of descending
velocities, the APs of other fibers will be recorded.
Note that: in this graph, the action potentials also have different heights or
amplitudes. This is because these are not single action potentials, but
aggregates of all APs in one type of fiber. In a mixed nerve, if A type of fibers
are more in number, the aggregate voltage of their APs will also be larger.

- 42 -
[Fig: Compound action potential.]

Study of excitability of tissues:

A. Rheobase: It is the weakest strength of the stimulus that can bring about
an excitation, when applied for any length of time to the tissue. In
practice, the weakest stimulus that brings about a response is called as
threshold stimulus or liminal stimulus. A stimulus having less than the
rheobase strength is called subliminal stimulus. (Rheobase is an
inconvenient tool to express the excitability of tissues, as the weakest
stimulus will have to be applied for a LONG DURATION. Applying [2 X
rheobase] is convenient as the response will be obtained in short
duration.)
B. Chronaxie: Time taken by a tissue to excite when twice the rheobase
strength is applied is called chronaxie.

- 43 -
 C. Utilization time: Time taken by a tissue to elicit a response when a
stimulus of a rheobase strength is applied.

Chronaxie is the measure of excitability of a tissue. Shorter the chronaxie, more

excitable is the tissue (as it excites in shorter time).

Strength-duration curve:
It is the graphic representation of the relation between strength of a stimulus
applied and the time taken by a tissue to excite.

[Fig: Strength-duration curve. Currents of various strengths are selected and

applied to a tissue. Time taken by the tissue to excite is plotted against the
various current strengths. (a) The minimum strength of the stimulus that excites
the tissue. It is the rheobase strength ~ 1 V in the graph. Time taken by the
tissue to excite, for this strength, is (b) in the graph and is called utilization time.
Then, [2 X rheobase] stimulus strength is applied to the tissue (2 V in the graph).
The tissue has taken 0.1 msec to excite; this duration is called chronaxie, (c) in
the graph.]

- 44 -
 Section 4

Muscle Physiology

[Introduction, Neuromuscular junction, Excitation-contraction coupling]

Learning objectives:

- It is important to understand how an electrical excitation, travelling

through a nerve, enters muscle and results in muscle contraction.

~ Introduction:

Muscle tissue constitutes almost 50% of the body – 40% is skeletal muscle +
10% is cardiac and smooth muscle.

➢ Muscle fibers are of two types according to microscopic appearance: (i)

striated muscle – has alternating light and dark bands which give striated
appearance. Skeletal muscle and cardiac muscle look striated. (ii) Smooth
muscle – no striations, smooth appearance.
➢ Skeletal muscle is under voluntary control; cardiac muscle and smooth
muscle are involuntary.

All types of muscles have one unique property: contractility. As the nerve impulse
enters the muscle, the muscle first excites electrically, and then it contracts.Skeletal
muscle contracts to move the limbs and body parts voluntarily. Cardiac muscle
contracts to pump the blood coming in chambers of the heart. Smooth muscle is in
the walls of viscera (G.I.tract, blood vessels, etc). It contracts to cause viscera
perform its functions (G.I. movements/peristalsis; blood vessel constriction,etc).

ALL THE DESCRIPTIONS IN MUSCLE PHYSIOLOGY ARE ABOUT SKELETAL MUSCLE,

UNLESS SPECIFIED OTHERWISE.

NEUROMUSCULAR JUNCTION (or Myoneural junction)

- 45 -
Introduction:

It is the “junctional region between a motor nerve and a muscle fiber”. A

(microscopic) gap exists between the motor nerve ending and the muscle
membrane, and yet an impulse from the nerve excites the muscle.

[Synapse is a broad term that describes junctional region between a nerve and
another cell; that another cell could be a nerve cell, or a muscle cell, or a gland.
Thus, neuromuscular junction is a type of synapse. For the sake of clarity, the nerve-
nerve junction is referred to as synapse, and a nerve-muscle junction is called
neuromuscular junction.]

An electrical impulse travelling through a nerve has to excite the muscle. However,
there is a gap between the nerve membrane and the muscle membrane. So, upon
reaching the nerve terminal, the impulse causes release of a chemical. This
chemical traverses the gap, reaches the muscle membrane, and causes electrical
excitation of the muscle. Thus, the events at the NM junction are: electrical —>
chemical —> electrical.

• Structure of the neuromuscular junction:

- 46 -
[Fig: Structure of NM junction. Motor neuron has an expanded ending on the
muscle. Motor end plate is that area of the muscle membrane which comes in
close contact with the nerve ending. Read the text below for description of NM
junction.]

A neuromuscular junction consists of the following structures:

A. Neuronal contents:

▪ The end of the motor neuron is swollen or expanded. It is called “terminal

button”. The membrane of the motor nerve (which is in apposition with the
muscle fiber) is called the “prejunctional membrane” (or ‘presynaptic
membrane’).

▪ The muscle fiber membrane where the motor neuron ends is called the
“postjunctional membrane” or “motor end plate”.

▪ Synaptic cleft or gutter:

- 47 -
 The space between the prejunctional membrane and the motor end plate is
called synaptic cleft or gutter. Its width is about 20-30 .

▪ There are two important structures present in the motor nerve ending:

1. Neurotransmitter vesicles – These are vesicles filled with the chemical

transmitter acetyl choline (Ach).

2. Mitochondria – to generate ATP for the synthesis of the acetyl choline.

▪ The prejunctional membrane has voltage-gated Ca++ channels (VGCC). [The

acetyl choline is present all the time in the nerve terminal. However, it
needs to be released when an AP arrives at the terminal. The voltage-gated
Ca++ channels sense the voltage change of the nerve membrane (that is, AP)
and they open, so that Ca++ from the ECF can enter the terminal. The
vesicles will then move toward the membrane and fuse with the
membrane. This fusion is brought about by the Ca++.]

▪ The prejunctional membrane also has “release sites”. The Ach vesicles fuse
here and discharge acetyl choline into the cleft.

B. Muscle contents:

▪ The postjunctional membrane (“motor end plate”) has the receptors for
acetyl choline.

- The acetyl choline receptors at the NM junction are “nicotinic

receptors” (AChR = Acetyl choline receptor)

- The Ach receptor is an example of “ligand-gated channel”. It has one

portion where the ligand (ACh) binds. This binding causes opening of
the channel within the receptor molecule. The channel then
facilitates the conductance of cations (Na+ & K+) through the muscle
membrane. {Entry of Na+ into the muscle will predominate over K+
exit, which will eventually lead to depolarization of the muscle.}

• Transmission of impulse across the NM junction:

- 48 -
 Impulse arrives at the motor nerve terminal

Voltage-gated Ca++ channels open; ECF Ca++ enters the nerve terminal

ACh vesicles migrate toward presynaptic membrane; they fuse with the membrane and
release ACh into the synaptic cleft by EXOCYTOSIS

ACh traverses the synaptic cleft and reaches the post-junctional membrane

ACh binds to its receptor on the motor end plate

Opening of the non-specific cation channel associated with the AchR

Increased conductance of Na+ & K+ through the channel; Na+ influx predominates over K+ exit.
Net influx of positive charges, resulting in depolarization of the muscle membrane

- 49 -
 • End-plate potential (EPP): (develops at motor end plate; stays at motor end
plate)

When the Na+ influx occurs through the postjunctional membrane, it does
not immediately burst into an action potential. Rather, it first causes
development of a localized, depolarizing potential which does not
propagate. It is called the “end-plate potential” (EPP).

Resting skeletal muscle has a membrane potential of - 90 mV. With the initial
entry of Na+ ions, it drops to a less negative value (say, - 50 mV). This 40 mV
depolarization of the motor-end plate is called EPP. EPP causes the muscle
membrane to cross the threshold and results in development of AP. The AP
then travels into the muscle. Thus, EPP is the forerunner of the AP.

Properties of EPP –

1. EPP is a graded response. IT DOES NOT OBEY “ALL-OR-NONE” LAW.

{Compare this with AP which obeys all-or-none law.}

2. EPP is localized response; IT DOES NOT PROPAGATE. {AP is a propagated

response.}

3. EPP is a monophasic response. A single event of depolarization of a

certain value occurs in EPP. AP is a biphasic response.

Video link ~ EPP

(localized potentials)
v/s AP

Miniature end-plate potential (MEPP) –

Even when the impulse is not arriving at the nerve terminal (that is, at rest),
some Ach vesicles at the terminal burst occasionally into the cleft. This gives rise to
a very small (“miniature”) potential (in V) on the motor-end plate. This is MEPP.
It is incapable of producing AP.

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 • Destruction of Ach:

An enzyme called cholinesterase (or acetyl cholinesterase) is present at the

NM junction {and at all the sites where Ach is released}. Immediately after
the release of Ach, it is destroyed by this enzyme (as the purpose of
excitation of the muscle is served).

Clinical application:

1. Myasthenia gravis – (myo = muscle; asthenia = weakness)

- It is an autoimmune disorder.

- Antibodies are developed (wrongly) against the Ach receptors on the

motor end plate. The receptors are destroyed, and the number of
receptors free to combine with Ach is reduced to 1/3rd or even less.

- There is failure of neuromuscular transmission with repetitive nerve

stimulation. Hence, there is early fatigue and weakness when
repeated contractions are attempted.

2. Anticholinesterases –

- These are the drugs that may be used in the treatment of myasthenia
gravis.

- They prevent the action of the cholinesterase enzyme on the acetyl

choline released at the NM junction. Ach will not be degraded
immediately after its release. It means, more of Ach will be available
at the NM junction, so that it can diffuse to the nearby end-plates and
act on the receptors that are still available for transmission.

- E.g. neostigmine.

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 Excitation-contraction coupling

[E-C coupling]

The concept –

The motor nerve sends the signals to a muscle to achieve muscle contraction.
The signals sent by the nerve are in the “electrical” format; that is, electrical
excitation (action potential) travels through the nerve. It causes electrical
excitation of the muscle. And this results in the muscle contraction. Contraction is
a “mechanical” type of event (actin – myosin interaction). Thus, two different types
of events (electrical & mechanical) have been “coupled” or combined. At some
point, electrical excitation ends and the mechanical contraction begins. This
coupling of two different types of events is called “excitation-contraction
coupling” [E-C coupling].

• Sarcotubular system of a skeletal muscle -

It is composed of tubular structures. It is a system of communication

between the outer sarcolemma (membrane of the muscle) and the interior
of the muscle.

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[Fig: Sarcotubular system and the proteins involved in E-C coupling.
Depolarization travels into the muscle via T-tubule —> sensed by DHPR —> DHPR
interacts with RyR —> Release of Ca++ into sarcoplasm —> Ca++ combines with
troponin C —> actin-myosin interaction starts (i.e., mechanical event).]

There are two types of tubules in a skeletal muscle.

1. Transverse tubules or T-tubules, and

2. Longitudinal tubules or L-tubules (or the sarcoplasmic reticulum)

(1) The T-tubules run transversely in the muscle. They begin at the muscle fiber
membrane and penetrate all the way from one side of the fiber to the
opposite side.

Where the T-tubules originate from the sarcolemma (muscle membrane),

they are open to the exterior. Therefore, they communicate with the ECF
surrounding the muscle fiber, and they themselves also contain ECF in their
lumens. In other words, the T-tubules are internal extensions of the muscle
membrane. Therefore, when an action potential spreads over a muscle fiber

- 53 -
 membrane, a potential change also spreads along the T-tubules to the deep
interior of the muscle fiber.

The T-tubules contain a voltage-sensitive protein called “dihydropyridine

receptor” [DHPR]. When depolarization travels deep into the muscle via T-
tubules, it causes a conformational change in the DHPR.

(2) The sarcoplasmic reticulum (SR) in the muscle is composed of the L-tubules
or longitudinal tubules. The L-tubules run parallel to the myofibrils (or along
the length of the fiber). The enlarged terminal portions of the L-tubules are
called “terminal cisternae”. Ca++ is stored in these terminal cisternae.

▪ The SR membrane contains Ca++-ATPase (or Ca++ pump). It pumps the

Ca++ from the sarcoplasm into the SR, thus keeping intracellular Ca++
concentration low.

▪ The SR contains a protein “calsequestrin”. Ca++ is loosely bound to it

and thus stored in the SR.

▪ SR contains a Ca++ release channel called “ryanodine receptor” (RyR).

RyR will interact with DHPR to cause release of Ca++ from the terminal
cisternae and initiate the muscle contraction.

A T-tubule and one terminal cistern on each side of the T-tubule together
compose the so-called “triad”. It is said that this is the place where
“coupling” occurs.

❖ The sequence of events in the E-C coupling:

1. Action potential arrives at the neuromuscular junction. Release of Ach

and its combination with postjunctional receptors causes depolarization
of the muscle membrane.

2. Depolarization travels deep down into the muscle via the T-tubules. The
voltage-sensitive DHPR undergoes a conformational change. It then
interacts with the RyR in the SR membrane.

- 54 -
 3. RyR (which is a Ca++ release channel) causes release of Ca++ from the
terminal cisternae into the sarcoplasm. This Ca++ then goes on to
combine with “troponin C” present on the thin (actin) filament in the
muscle fiber.

4. A conformational change in the troponin leads to troponin-tropomyosin

complex to expose the ‘active sites’ on the actin filament. Myosin
molecules now interact with the ‘active sites’. This results in muscle
contraction.

Note: Up to the release of Ca++ from the SR, the events are electrical (APs). After
the release of Ca++, the mechanical events (of contraction) begin. Hence, Ca++ is said
to be the “coupling agent” between electrical excitation and mechanical process
of contraction.

~ Clinical application-

➢ Malignant hyperthermia:

In some people, there is a genetic defect; the gene that encodes the RyR
protein in the SR membrane is defective.

When such persons are administered an inhalational anaesthetic

(halothane/ether) or a skeletal muscle relaxant (succinyl choline) before a
surgery, the defective RyR causes excessive release of Ca++ in the
sarcoplasm. This increases muscle contractions and muscle metabolism
tremendously, causing excessive heat generation (hyperthermia) in the
muscles.

[Note: It is not a malignancy or cancer.]

- 55 -
 Section 5

Sarcomere; Changes during muscle contraction

Learning objectives:

- Skeletal muscle microscopic structure gives insights into the

contraction mechanisms. Understanding the contractile machinery
has implications in sports & exercise science.
- Abnormalities or genetic defects in muscle proteins result in
debilitating morbid conditions. It is imperative to understand
microscopic structure of muscle and its constituent proteins, in
order to learn the disease conditions affecting muscles.

~ Physiologic anatomy of skeletal muscle-

➢ The skeletal muscle is made up of muscle fibers (or muscle cells). The cell
membrane of the muscle fiber is called sarcolemma. The sarcolemma
consists of a true cell membrane, called the plasma membrane, and an
outer coat made up of glycoprotein. The tight connection between the
sarcolemma and the surrounding connective tissue structures makes it
possible for the force developed by the muscle fibers to be transmitted
effectively to the tendons.
➢ Each muscle fiber is surrounded by a sheath called endomysium. About
20 muscle fibers are grouped into fascicles which are covered by a
connective tissue sheath called perimysium.

~ Sarcomere:

- 56 -
[Fig: It shows a sarcomere, with filaments, bands/zones in the sarcomere. Note:
1 sarcomere = 1 full A-band + 2 half I-bands. Refer to text for details.]

Each muscle fiber is divided into several myofibrils.

➢ Each myofibril extends from one end of the muscle fiber to the other.
➢ Each myofibril is composed of muscle filaments which are actually
responsible for muscle contraction. Each myofibril is composed of about
1500 myosin/thick filaments and 3000 actin/thin filaments; the filaments
are large, polymerized protein molecules.
➢ The myofibrils are divided into functional units, or sarcomeres, by a
transverse sheet of protein, called the Z disc. The Z discs of neighboring
myofibrils are lined up with each other so that a Z line is created which
spans the entire width of the fiber. Thus, myofibrils are attached to one
another all the way across the entire muscle fiber.
➢ The Z discs are placed at every 2  distance in the fiber. Portion of the
fiber between two successive Z discs is called sarcomere. Arising on either

- 57 -
 side of the Z disc are ACTIN or thin filaments. One end of the thin filament
is attached to the Z disc and the other end extends toward the center of
the sarcomere.
➢ The thick filaments or MYOSIN filaments are interspersed between the
thin filaments; they are not attached to the Z disc. Projections from the
thick filaments called cross-bridges extend toward the thin filaments.
Interaction between these cross-bridges and the actin filaments causes
muscle contraction.
➢ The side-by-side relationship between the myosin and actin is maintained
by a large filamentous protein called titin. This is the largest protein
molecule in the body.
➢ The interdigitating thick and thin filaments create the pattern of light and
dark bands which gives striated appearance to the muscle.
▪ On either side of the Z discs, for some distance, there are only thin
filaments. This creates light areas called I bands. (I = isotropic to
polarized light)
▪ Toward the center of sarcomere, overlap of thick and thin filaments
creates dark areas called A bands. (A = anisotropic to polarized
light)
▪ At the very center of A band, there are only thick filaments. This
area is called H zone. At the very center of H zone is the area of
darkness called M line, here the thick filaments do not contain any
cross bridges.
▪ The dark M-line plus the light areas on either side constitute the so-
called pseudo-H zones.

➢ 1 sarcomere = 1 full A band + 2 half I bands

~ General mechanism of muscle contraction-

Sliding filament theory

- 58 -
 - Muscle contraction involves shortening of the muscle fibers; there
would be shortening of all the sarcomeres.
- All the Z-lines are pulled inward. This decreases the length of the
sarcomere.
- Thin filaments slide over the thick filaments. The thin filaments are
pulled to each other, toward the centers of their respective
sarcomeres.

Sarcomere changes that occur with muscle contraction:

[Fig: It shows changes in sarcomere with muscle contraction. Shortening of all

sarcomeres would occur with contraction of the fiber. Z-lines are pulled inward
and thin filaments slide over thick filaments. Note ~ Length of the thick filament
remains unchanged; hence, A-band remains unchanged.]

• I-band shortens
• H-zone disappears (as ends of the thin filaments begin to overlap near the
center of the sarcomere)

- 59 -
 • M-line becomes prominent (due to the overlapping ends of the thin
filaments)
• A-band remains unchanged. (Length of the A-band is same as length of
thick filament. There is no change in the length of thick filaments during
contraction.)

Molecular basis of muscle contraction:

(It describes the molecules that constitute thick & thin filaments, and their
interaction which results in muscle contraction.)

(1) Thick filament-

➢ The thick filament is composed of about 500 myosin molecules.
➢ Each myosin molecule is composed of six polypeptide chains – two heavy
chains and four light chains.
- Two heavy chains are called heavy meromyosin (HMM)
- Four light chains are referred to as light meromyosin (LMM)

[Fig: A myosin molecule. Refer to text for description.]

- 60 -
 ➢ The two heavy chains wrap spirally around each other to form a double
helix. One end of each heavy chain is folded into a globular polypeptide
structure called the myosin head. The four light chains are present in the
myosin head. The remaining part of the molecule is the double helix – the
body and tail.
➢ The tails of the myosin molecules are bundled together to form the body
of the thick filament; and the heads and some parts of the molecules hang
out from the filament. These protruding portions are called “cross-
bridges”.
➢ Myosin head has ATPase activity. It cleaves ATP to energize the
contraction process.
(2) Actin (thin) filament-
It is composed of three protein components: actin, troponin, and
tropomyosin.

[Fig: Constituents of thin filament. Two chains of actin molecules and

tropomyosin (shown in red) coiling around the actin chain. Also shown is troponin
molecule with its 3 parts – C, T, and I.]

➢ Actin - The backbone of the thin filament is formed by two chains of actin
molecules, which wind around each other. (These are called “F-actin”

- 61 -
 helix; each F-actin strand is made up of polymerized G-actin molecules.)
Each actin molecule has a myosin binding site or “active site”. Interaction
between these active sites of actin and the heads of the myosin leads to
muscle contraction.
➢ Tropomyosin - In resting state, the myosin binding site or the “active site”
is covered by another thin filament protein: tropomyosin. This long
molecule coils around the actin chain. When muscle is relaxed,
tropomyosin covers the active sites of actin so that they do not interact
with myosin heads.
➢ Troponin – The position of tropomyosin on the thin filament is controlled
by another protein: troponin. It is a complex of 3 subunits. (i) troponin C
: has high affinity for Ca++;
(ii) troponin T : has high affinity for tropomyosin; and
(iii) troponin I: has high affinity for actin.
When Ca++ combines with troponin C, troponin undergoes a
conformational change that causes tropomyosin to move away from its
position covering the active sites on actin.

~ “Ratchet theory” or “walk-along” theory of muscle contraction:

• When muscle is in a relaxed state, the “active sites” over the thin filaments
are kept covered by the troponin-tropomyosin complex.
• When impulse arrives in the muscle, Ca++ from terminal cisternae is released
in sarcoplasm. The Ca++ then combines with troponin C. This initiates the
actin-myosin interaction.

Video link ~ Cross bridge cycling: Muscle shortening and tension

generation

- 62 -
[Fig: It shows cross bridges. Myosin heads, coming in contact with the ‘active
sites’ over thin filaments, form the cross bridges.]

➢ Muscle contraction (shortening & tension generation) occurs by cross-

bridge cycling.
➢ The first step in the cross-bridge cycle is the binding of actin and myosin.
This occurs spontaneously, after Ca++ binds to troponin C, and
tropomyosin moves away from its position blocking the myosin binding
site on actin.
➢ The second step is the bending of the cross-bridge and the sliding of the
thin filament across the thick filament. The myosin head attaches to the
active site on actin. Then, the myosin head is tilted, and it creates a force
called “power stroke” that drags or pulls the actin filament inward.
➢ The third step is detachment of the myosin head from the thin filament.
For the detachment to occur, the products of ATP
hydrolysis must be removed from the cross-bridge and a new molecule of
ATP put in their place.
➢ In the final step, the cross-bridge returns to its original upright position.
It now combines with the next active site farther down along the thin

- 63 -
 filament; then the head tilts again to cause a new power stroke, and actin
filament is pulled inward.

Thus, the heads of the cross-bridges bend back and forth and step by step walk
along the actin filament, pulling the actin filaments toward the center of the
sarcomere. This is called “walk-along theory” of muscle contraction.

The cross-bridges attach to actin, then detach and again attach to the next active
site of actin. This is called “cross-bridge cycling”. The greater the number of cross-
bridges in contact with the actin filament at any given time, greater will be the force
of contraction or tension in the muscle.

Applied Physiology:

➢ Rigor mortis: (Muscle stiffness after death)

- Detachment of myosin heads, from the ‘active sites’ of thin
filaments, is necessary for the muscle to relax.
- The detachment of myosin head requires ATP.
- There is lack of ATP after death. Hence, myosin heads can not detach
from ‘active sites’.
- Since myosin heads remain attached to thin filaments, muscles
become stiff or rigid.

- 64 -
~ Role of ATP:

When a muscle contracts, work is performed and ATP is cleaved. Greater the
amount of work performed by the muscle, greater is the amount of ATP cleaved.
This is called Fenn effect.

Before contraction begins, the heads of the cross-bridges bind with ATP. The
ATPase activity of the myosin head cleaves the ATP but the cleavage products (ADP
& Pi) remain bound to the head. Now, as the contraction begins, heads attach to
the actin filament. This generates tension in the muscle. For the detachment of the
head from actin, the cleavage products of ATP must be removed from the myosin
head and a new molecule of ATP put in their place.

~ Relaxation of the muscle:

There are Ca++ pumps (Ca++-ATPase) on the membrane of the sarcoplasmic

reticulum in muscle. They remove Ca++, by active transport process, from the
sarcoplasm. The sarcoplasmic Ca++ concentration falls, troponin returns to its
original conformational state, tropomyosin moves back to cover the “active site”
on actin. Cross-bridge cycling stops; and the muscle relaxes.

{Note two points here: (i) Ca++ concentration of sarcoplasm should fall, to cause
muscle relaxation. (ii) Ca++ removal is an active transport process, by Ca++ - ATPase
pump. Thus, muscle relaxation is an “active” process.}

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[Fig: The SERCA pumps the Ca++ out of the sarcoplasm, back into the terminal
cisternae. As sarcoplasmic Ca++ falls, cross-bridge cycling stops and muscle
relaxes.]

Video link ~ Depolarization/repolarization; contraction/relaxation.

What’s the relation?

- 66 -
 Section 6

Factors influencing the force of contraction of the muscle:

(Factors determining the tension development)

Learning objectives:

- Strength of contraction has applicability in sports and exercise

science. Some sports need single best contractions; others need
bursts of strong contractions in short time.
This section explains the factors that cause variations in the strength
of contraction.

1. Length – tension relationship (Starling’s law)

2. Frequency – tension relationship (staircase, tetanus, etc)
3. Load acting against the muscle contraction
4. Fatigue in the muscle
5. Number of motor units active during contraction
6. Number of muscle fibers per motor unit.

(1) Length – tension relationship: (STARLING’S LAW)

The force of contraction of a muscle is proportional to the initial length of
muscle fiber or sarcomere. When the muscle is about to begin to contract, if
its fiber length is more, the strength of contraction is proportionately
greater. This is called “straling’s law”.
“Within physiological limits, the strength of contraction of a muscle is
proportional to the initial length of the muscle fiber; greater the initial
length, stronger the contraction.”
Explanation:
The resting length of the sarcomere is about 2 . At this length, there
is some degree of overlap of myosin and actin filaments. When the fiber is

- 67 -
 stretched, that is its resting length is increased, the length of the sarcomere
also increases. Now, there is more and more actin – myosin interdigitation
possible, resulting in stronger and stronger contraction. At 2.2  length of
the sarcomere (which is called LO or length optimum for sarcomere), there is
strongest contraction of muscle. If the sarcomere length is increased further,
however, the actin – myosin interaction will be reduced.
(2) Frequency – tension relationship: (staircase, tetanus, etc)
An isolated contraction of a muscle is often called a “twitch”. If the muscle is
connected to a writing lever, the lever moves up during muscle contraction
and goes down as the muscle relaxes. If this movement of the lever is
recorded on revolving drum, it gives a curve form – the “simple muscle
curve”.

[Fig: Single stimulus was applied to muscle. There is a single muscle contraction
followed by relaxation. C-H is the height of contraction, which indicates strength
of the contraction.]

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Now, if the muscle is stimulated twice, in quick succession, two contractions and
relaxations will record two curves. All factors are the same, and are held constant.
Just, in place of a single stimulus, two stimuli were given in quick succession.

[Fig: Two successive stimuli applied to the muscle. Two contractions occurred;
second contraction was stronger (as indicated by its height). If all the factors were
the same, and just that two stimuli were given instead if one, how is it that the
second contraction automatically became stronger?]

Note that: Second curve has more height compared to the first one. It means,
second contraction was stronger compared to the first one. If same stimulus was
applied, and all other things were also constant, then why second contraction was
stronger?

Ans:- Beneficial effect.

- 69 -
 When a muscle is stimulated twice, in quick succession, it produces two
contractions. The first contraction causes some changes in the muscle which are
said to be “beneficial” for the second contraction. The changes are – decreased
viscosity and increased temperature in the muscle due to the first contraction. The
possible explanation is: decreased viscosity causes easier sliding of filaments, thus
better actin-myosin interaction possible for second contraction. Increased
temperature would increase the activity of the channels.

➢ Staircase/treppe:
If the muscle is stimulated with increasing frequency, 5 or 10 stimuli per
second in quick succession, the beneficial effect will be further extended.
Each successive contraction will be stronger than the preceding one. This
gives a record which resembles staircase.

[Fig: Staircase. 5 stimuli applied to muscle, in quick succession.]

This is called “staircase effect”. (Bowditch was the research worker who called it
“treppe” (German word: it means staircase).

Explanation: Two possible mechanisms – (i) beneficial effect: Each contraction

makes it easier for the next contraction; thus contractions become stronger and
stronger. (ii) Intracellular calcium: each stimulus causes Ca++ from muscle tubules
to come into the sarcoplasm; and sarcoplasmic Ca++ to increase. This Ca++ is going

- 70 -
to combine with troponin C to initiate contraction. STRENGTH OF CONTRACTION
IS PROPORTIONAL TO THE SARCOPLASMIC Ca++ LEVELS.

➢ Tetanus:
If the muscle is stimulated with even higher frequency (say, 20 times in a
second), then a sustained state of contraction of the muscle is observed.
This sustained contraction and failure of relaxation of the muscle is called
tetanus.

Video link ~ Tetanus: The first thing that should come to mind is
“HIGH FREQUENCY”
stimulation

- 71 -
[Fig: Tetanus, resulting from high frequency stimulation of a muscle.]

The graph shows initiation of first contraction, and then all the further contractions
have fused. There is no relaxation seen.

Reason: Let us recall that, for the muscle relaxation to occur, Ca++ that came into
the sarcoplasm has to be pumped out by a Ca++ - ATPase pump. If we stimulate a
muscle with very high frequency, each stimulus is very close to the previous
stimulus. The Ca++ that comes in the sarcoplasm with first stimulus cannot be
pumped out; in fact, with every stimulus Ca++ keeps coming into the sarcoplasm.
Obviously, muscle will remain contracted and will fail to relax. (A somewhat similar
phenomenon is observed when one is writing exam papers. Due to high frequency
stimulation of hand muscles, the muscles sometimes remain contracted for a
while.)

In summary, the strength of contraction is influenced by the frequency of

stimulation of the muscle.

(3) Load acting on the muscle:

If a load is applied to the muscle, it opposes muscle contraction and the
strength of contraction decreases. Muscle creates a force to lift the load, but
load is a reverse force that opposes contractile force. The net force available
is thus reduced.
Concept of pre-load v/s after-load-
When the muscle is not supported and a load is applied to the muscle when
it is resting, load starts acting on the muscle straightaway. This is even before
the contraction has begun. It is called pre-load. (When we carry a bucket full
of water, the biceps is not contracting. Yet the load is acting on the biceps by
stretching it in its resting condition. This is an example of pre-load.) Note
that, once the muscle contraction begins, the load will oppose the
contraction. Thus, load is acting on the muscle during relaxed state as well as
during contraction. {Since the load is acting freely on the muscle, some
authors call it free load.}
When the muscle is supported and a load is applied to it during resting state,
it does not stretch the muscle. However, when the muscle contraction

- 72 -
 begins, it now has to lift the load. Thus, the load is acting on the muscle only
after the contraction has begun. This is called after-load. (If we lift a bucket
full of water with biceps contraction, it is an example of after-load.)
{Note that: in both pre-load and after-load, load is acting on the muscle
during contraction. However, in pre-load, load starts acting on the muscle
even before contraction begins.}
PRE-LOAD CAUSES STRONGER MUSCLE CONTRACTIONS DURING INITIAL
LESSER LOADS.
As we start applying the load in gradually increasing fashion, initially the
contraction will be stronger. REASON: STARLING’S LAW. As we apply the
load and it starts stretching muscle in resting state, it increases the length of
the muscle fiber/sarcomere. By Starling’s law, more the initial length,
stronger will be the contraction. But this is only upto physiological limits for
the muscle. Further addition of load will stretch the muscle and increase fiber
length beyond physiological limits. Then, the contraction strength will
reduce.
(4) Fatigue:
If a muscle is stimulated repeatedly for a longer time, its contractile strength
goes on decreasing gradually. This gradual failure of the muscle to respond
is called “fatigue”.
The repeated impulses are sent by the nerve to the muscle. It has been
shown that the nerve does not ever fatigue, and the muscle also does not
fatigue. The seat of fatigue is the neuromuscular junction.
With repeated stimulation, the neurotransmitter acetyl choline begins to
exhaust from the nerve terminals. (Read neuromuscular junction for details.)
The muscle contraction reduces gradually because the motor units of the
muscle stop responding one-by-one. And, this happens because nerve
branches (of motor units) exhaust their acetyl choline one-by-one. Fatigue is
also shown to be due to depletion of nutrients (glycogen).
(5) Number of motor units active during contraction, and
(6) Number of muscle fibers in a motor unit
Each motor neuron that leaves the spinal cord innervates multiple muscle
fibers.

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 Motor unit:
A motor neuron, all its branches, and the muscle fibers supplied by
them are together called a motor unit. In the muscles which react rapidly
and perform fine activity, the motor units are small; only 2-3 fibers in a motor
unit. In large muscles that perform gross activity, there may be 200-300
fibers in a motor unit.
The point that should be noted is: all the muscle fibers in a motor unit
always contract together.
Recruitment of the motor units:
With weaker stimulus, a few motor units will contract. As the stimulus
strength is increased, more and more motor units will start contracting; thus
contraction will become stronger. At some point, all the motor units in the
muscle will be involved in contraction. This is the strongest possible
contraction for the muscle. That is, contraction strength cannot increase
further.

Video link ~ Sarcomere is the ‘structural’ unit; motor unit is the ‘functional’
unit for a muscle.

~ Energetics of muscle contraction-

Most of the energy required for muscle contraction is required for cross-
bridge cycling during the contraction. Small amount of energy is also required to
bring about muscle relaxation (Ca++ - ATPase; to pump calcium out of sarcoplasm).

If there is a continuous muscle contraction, as in exercise, following energy sources

are utilized:-

There are stores of ATP in the muscle. However, they can sustain muscle
contractions only for 1- 2 seconds. Once this ATP is cleaved and ADP is formed, the
ATP will have to be reconstituted so that muscle contraction can continue. This ATP
resynthesis or formation occurs due to following sources:

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 (i) Phosphagen system (creatine phosphate in muscle/phosphocreatine):
It consists of creatine with high energy phosphate attached to it. It
donates this high energy phosphate to the ADP that was formed early.
Thus, ATP will be reconstituted instantly. This ATP can continue to
energize the muscle contraction further. This reaction is called “Lohmann
reaction”. (This reaction is similar to a water tank which is getting filled
from above and its tap is open so that water is flowing out also. ATP is
being formed and utilized simultaneously.)
This can energize muscle contraction only for next 5 to 8 seconds.
(ii) Glycogen – lactic acid system:
The next important source of energy is glycogen stores in the muscle.
Rapid enzymatic breakdown of the glycogen to pyruvic acid and lactic acid
liberates energy that is used to resynthesize ATP and phosphocreatine.
It can energize muscle contraction for next upto 1 minute.
Significance:
These reactions can occur in the absence of oxygen.
They are very rapid reactions.
(iii) Oxidative metabolism:
The third and final source of energy is oxidative phosphorylation. More
than 95% of energy used by muscles for sustained, long-term contraction
is derived from this source.
It can energize muscle contraction for hours.

Types of fibers in skeletal muscle:

The skeletal muscles are composed of a mixture of muscle fibers. There are
mainly two types of muscle fibers: (i) fast glycolytic or pale, and (ii) slow oxidative
or red fibers.

The muscle fibers that are involved in rapid contraction are “fast” type of fibers.
They are fast because energy is mainly derived from glycolysis (rapid energy
source). The fibers that induce slow but sustained contractions are “slow” type of
fibers. Main energy source for these is oxidative metabolism.

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 Fast glycolytic fibers Slow oxidative fibers
Large fibers for strong contraction Small fibers
Extensive sarcoplasmic reticulum for Comparatively, less extensive
rapid release of Ca++ to initiate sarcoplasmic reticulum
contraction
Large amounts of glycolytic enzymes Lesser amounts of glycolytic enzymes
(relatively)
Less extensive vascularity because Extensive blood vessel system to supply
oxidative metabolism is less important extra amounts of oxygen
(less oxygen required)
Fewer mitochondria (because oxidative More number of mitochondria(because
metabolism, which occurs in energy is derived from oxidative
mitochondria, is less important metabolism which occurs in
mitochondria)
Less amount of myoglobin (myoglobin More amount of myoglobin (an iron-
in muscle; for uptake of oxygen and to containing protein similar to
deliver it to mitochondria); hence fibers hemoglobin; it stores oxygen in
look pale muscle); it gives red appearance to
fibers
Rapid contractions, smaller duration Slow contractile activity of long
(100 m sprint event) duration (10 km marathon)

Types of muscle contraction:-

(Recall here, that a muscle contraction involves two changes – (i) tension is
generated in the muscle, and (ii) muscle shortening happens.)

(Isometric v/s isotonic contraction)

(1) Isometric contraction: (iso = same; metric = length)

In such contractions, the length of the muscle does not change. That is,
muscle shortening does not occur during contraction. Only tension is
generated in the muscle.
(2) Isotonic contraction: (tone = tension) Tension remains the same

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 Once a certain tension is built up in the muscle, muscle shortening will occur
for the same amount of tension. Thus, tension remains the same.

Video link ~ Isometric v/s isotonic

contraction; with example

During isotonic contraction, muscle is shortening. Thus, it moves the load through
a distance. Hence, work is done during such contraction. (Work done = load ×
displacement)

During isometric contraction, only tension is generated in the muscle. But, muscle
shortening does not occur. It does not displace a load. Hence, work is NOT done
during isometric contraction. Most of the energy is spent as heat.

Thus, heat production is greater during isometric contraction, whereas work is

done during isotonic contraction.

{Note that: No contraction is purely isotonic or purely isometric. Imagine lifting a

moderately heavy load with biceps – flexion at elbow. Initially, the muscle
generates tension which creates a force that can displace the load. Once such
tension is generated (that is, isometric contraction) muscle starts shortening and
lifting the load. Now, the tension of the muscle remains constant but muscle length
is changing. This is isotonic contraction.}

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 Section 7

Smooth muscle

Learning objectives:

- Smooth muscle structure and contractile properties are different, as

compared to skeletal muscle. This section is about learning of
smooth muscle contraction – How smooth muscle can produce
sustained or continuous contractions, with lesser energy expenditure.
- The section also introduces some basic characteristics of cardiac
muscle properties.

• Smooth muscle lines the viscera (e.g., GIT), blood vessels.

• Since actin-myosin filaments are not arranged into sarcomeres, the cells
appear non-striated/smooth. Smooth muscle is not under voluntary control.

• Types: (1) single-unit (unitary) smooth muscle, and (2) multiunit smooth
muscle.

1. Single-unit smooth muscle:

- It is the predominant type; also called visceral smooth muscle as it is

present and regulates activities of viscera such as G.I.T., urinary
bladder, uterus, etc.

- Functions as syncytium. Cells connected by gap junctions allow rapid

spread of charges from one cell to the next, resulting in simultaneous
contraction of many cells.

- G.I. smooth muscle show rhythmic fluctuations of membrane

potential (called slow waves); there are spikes at the peak of these
slow waves. They lead to muscle contraction. Thus, pacemaker
activity is exhibited by these cells. In the periods of quiescence,
membrane potential is about - 50 mV.

2. Multiunit smooth muscle:

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 - No gap junctions; each fiber is innervated separately (as in skeletal
muscle).

- No pacemaker activity; this type of smooth muscle is under ANS

control.

- Iris, ciliary muscle, vas deferens, arrector pili in the skin have this
type of smooth muscle.

Structure and properties:

[Fig: Sarcomere in a smooth muscle fiber. Instead of Z-lines, there are dense bodies at regular
distances. Thin filaments arise on either side of the dense bodies (though shown only on one
side, in the diagram).]

• No Z-discs; thin filaments are attached to dense bodies. Actin : myosin ratio
is about 15:1. (in skeletal muscle ~ 2:1)

• T-tubules are absent or rudimentary. The sarcolemma has tiny sac-like in-
pocketings called caveolae.

• Smooth muscle contains fewer mitochondria; it mainly depends on

glycolysis for its metabolic needs.

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 • No troponin-tropomyosin complex to prevent myosin binding of actin.
Myosin cross-bridges need to be activated; the activation requires that one
of the light-chain proteins in the myosin head be phosphorylated. Myosin
phosphorylation is catalyzed by myosin light-chain kinase (MLCK). When
Ca++ combines with calmodulin, there is activation of MLCK. (Another
difference: instead of troponin C, Ca++ combines with calmodulin.)

• Myosin phosphatase removes phosphate from the myosin light-chain

protein, cross-bridge cycling ceases and relaxation occurs.

• Velocity of shortening or rate of cross-bridge cycling is dependent on

phosphorylation of the myosin light chain.

• Dephosphorylated cross-bridges remain attached to the actin – these are

“latch-bridges”. Thus, a sustained tension is developed in the muscle due to
these latch-bridges without much energy consumption.

• Visceral smooth muscle is unique in that, unlike other types of muscle, it

contracts when stretched in the absence of any extrinsic innervation.

CARDIAC MUSCLE:

• The cardiac muscle, at Z lines, has intercalated discs; they provide a

combination of mechanical junctions and electrical connections. (1) The
mechanical connections ∼ fascia adherens and desmosomes. They keep the
cells from pulling apart when contracting. (2) The electrical connections ∼ gap
junctions between cardiac muscle cells allow propagation of the AP
throughout the heart.

• The basic organization of thick and thin filaments in cardiac muscle cells is
similar to that seen in skeletal muscle. Hence, cardiac muscle is classified as a
striated muscle.

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• Each thick filament is surrounded by six thin filaments, and each thin filament
receives cross-bridge attachments from three thick filaments. This complex
array of thick and thin filaments is characteristic of both cardiac & skeletal
muscle and helps stabilize the filaments during muscle contraction.

• Myofibrils are surrounded by the sarcoplasmic reticulum (SR). It is similar to

skeletal muscle except that the SR in the heart is less dense and not as well
developed. T-tubules are the invaginations of the sarcolemma (comparable to
those seen in skeletal muscle); however, they are positioned at the Z-lines (in
skeletal muscle, they are positioned at the ends of the I-bands). In cardiac
muscle, there also tends to be fewer and less developed connections between
the T-tubules and the SR than in the skeletal muscle.

• Excitation-contraction coupling:

[Figure: Excitation-contraction coupling in cardiac muscle. When impulse

arrives, it is sensed by DHPR, which itself then opens and allows ECF Ca++ to flow
into the muscle. This Ca++ causes further release of intracellular Ca++ via RyR.]

THE HEART REQUIRES EXTRACELLULAR Ca++ TO CONTRACT.

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The AP in cardiac muscle, as it travels along the T-tubules, is sensed by the
voltage-gated L-type Ca++ channel in the sarcolemma. As these channels open, a
relatively small amount Ca++ from ECF enters the cardiac muscle. It triggers the
release of further Ca++ rom the SR (“Ca++ sparks”). The influx of Ca++ is responsible
for the plateau phase of the AP, and is also critical for triggering release of Ca++
from the SR and thus initiating contraction.

o The L-type Ca++ channel is composed of five subunits ∼ α1, α2, β, γ, and δ.
The α1 subunit is also called the dihydropyridine receptor (DHPR) because it
binds the dihydropyridine class of Ca++ channel blockers (e.g. nifedipine).
Although this channel complex is present in both skeletal and cardiac
muscle, it serves very different functions in the two muscle types. In skeletal
muscle ∼ Ca++ release from the SR does not involve entry of Ca++ across the
sarcolemma but instead results from a voltage-induced conformational
change in the DHPR. Thus, E-C coupling in cardiac muscle is termed
ELECTROCHEMICAL COUPLING (involving Ca++-induced Ca++ release),
whereas E-C coupling in skeletal muscle is termed ELECTROMECHANICAL
COUPLING (involving direct interactions between the DHPR in the T tubule
and the RYR in the SR.)

o Ryanodine receptors (RYRs) ∼ In each cardiac muscle sarcomere, terminal

regions of the SR abut T tubules and the sarcolemma. These junctional
regions of the SR are enriched in ryanodine receptors (RYRs). The RYR is a
Ca++-gated Ca++ channel; influx of Ca++ during an AP is able to initiate release
of Ca++, via this channel, from the SR into the sarcoplasm.

Contraction mechanism of cardiac muscle:

- Contraction of cardiac muscle is thin filament regulated (as in skeletal

muscle). That is ∼ rise in cytosolic [Ca++] and binding of Ca++ to
troponin C results in a conformational change in the
troponin/tropomyosin complex, and myosin-binding sites on the actin
(thin) filament are exposed. This will initiate actin-myosin interaction.

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