Muscle Physiology

Presenter: Dr Irene
Study objectives

At the end of this topic, you have to be able to describe the following:

• Structure of skeletal, cardiac and smooth muscles.

• Excitation contraction coupling of each type of muscle.

• Clinical implication on skeletal, cardiac and smooth muscle..

Skeletal Muscle
Introduction
• A muscle is covered by a fibrous connective tissue sheath called
epimysium which extend as tendons
• A muscle is composed bundles of columns called fascicles divided and
covered by a connective tissue sheath called perimysium
• A fasciculus is composed of several muscle fibers called myofibril
covered by a connective tissue sheath called endomysium
Cont..
Skeletal muscle
• Skeletal muscles are usually
attached to bone on each end by
tough connective tissue “tendons”
• When it contracts, it places tension
on its tendons and attached bones
• The tension causes movement of
the bones at a joint
Characteristics of Skeletal Muscle
• Striated
• Capable of rapid and strong contractions
• Attached to the skeleton
• Under voluntary and involuntary nervous control
• Multinucleated
 Skeletal muscle fiber
• A cylindrical muscle cell
• Each is surrounded by a plasma
membrane, called sarcolemma
• Enclosed is sarcoplasm: an
intracellular fluid filled area
between myofibril containing
contractile filaments, ions,
enzymes and mitochondria
• Sarcoplasmic reticulum: extensive
reticulum surrounding a myofibril
 Myofibrils
• Myofibrils comprises 3 types of protein
Contractile proteins
 myosin and actin

Regulatory proteins
 troponin and tropomyosin
 Initiate and terminate contraction

Structural proteins
 titin, myomesin, nebulin and dystrophin
 Provide proper alignment, elasticity and extensibility
Myofilaments: Contractile Filaments
• Two types: thick myosin and thin actin
filaments

• Partially interdigitate giving appearance

of dark and light bands
• Dark (A) bands has Myosin and ends
of actin filaments
• Light (I) bands has Actin only

• A filamentous protein (Z) disc anchors

filaments of one myofibril and myofibril
to one another
Cont..
• Each unit is a sarcomere;
delineated by Z- lines
 A-band is dark (overlapping
actin and myosin)
 I-band is light (actin only)
 H zone: part of the A band that
contains only myosin fibers
 M line: center of the H zone
(holds myosin fibers in place)
Myosin Filaments
• Made of many myosin protein
molecules bundled together to form a
filament
• Has 6 polypeptide chains
• Heavy chains wrap around each
other to form a spiral double helix
tail
• At the end of tail all chains fold to
form a globular head
• Heads projects away towards the
actin filament forming so called
cross bridge
Actin Filaments
• Complex composed of 3 protein
molecules
i. Actin protein
• Made of G actin protein polymerized
to form F helix
a backbone spiral helix

• G actin is a molecule forms active

site for cross bridge binding during
sliding mechanism of muscle
contraction
 Cont..
ii. Tropomyosin protein
• Helix wraps spirally around F actin
helix covering active sites in a muscle
resting state

iii. Troponin
• Binds on sides along Tropomyosin at
intermittent points
• Composed of 3 globular protein sub
units: Troponin I has affinity for actin,
T has affinity for Tropomyosin while
C has affinity for Ca2+ ion
Cont..
Excitation-Contraction Coupling of Skeletal
Muscle

.
General mechanism of muscle contraction
•Involve the following steps
 An action potential transmitted by motor neuron
reaches neuromuscular junction
 Nerve ending releases neurotransmitter ACh
 ACh bind to receptors stimulating ACh gated Na+
chanels to open allowing influx of Na+ ions into a
myofibril
Stimulation of the muscle cause an increase in Ca2+ levels of muscle fibres
Ca2+ then binds to the troponin which cause tropomyosin to uncover myosin
binding parts of the actin
Myosin head binds to actin, ADP and P are released
Myosin head bends and pushes the actin
ATP then binds to the myosin head and releases the actin, then the ATP molecule
then hydrolyse to ADP and P, and myosin head binds to the actin again etc
When stimulation is finished, Ca2+ decreases and troponin-tropomyosin complex
return to the default stage
Potent Ca2+ pump located on SR pumps ion back into reticulum for the next
action potential
 Role of energy
• Energy required to
perform work of
contraction is supplied by
cleaving ATP into ADP and
Pi
• Myosin head has ATPase
activity
• Fenn effect: the greater
the work performed by a
muscle the greater the
amount of ATP cleaved
Walk Along (Ratchet) Theory of Muscle Contraction
Contraction of striated muscle
• The shortening of striated
muscle is brought about by
the thick filaments pulling
the thin filaments towards
the centre of the sarcomere,
thereby making the H zone
and I bands shorter. The A
band stays the same length.
None of the filaments
shorten, but the sarcomere
shortens – the sliding
filament theory of muscle
contraction
Clinical application

.
 Muscular Dystrophies
 A group of inherited diseases that
damage and weaken your muscles
over time
 Sarcolemma tears during muscle
contraction
 This damage and weakness is due
to the lack of a protein called
dystrophin,
 Dystrophin: is necessary for normal
muscle function
Rigor mortis
• State of contracture of all muscles of
the body several hours after death.
• This rigidity results from loss of all
the ATP, which is required to cause
separation of the cross-bridges.
• Ca+2 ions leak out of the SR and
allow myosin heads to bind to actin
• cross-bridges cannot detach from
actin until proteolytic enzymes begin
to digest the decomposing cells
Myasthenia gravis
• An autoimmune disease causing
severe muscle weakness
• Caused by own antibodies,
produced by their own immune
system, that bind to attack and
block their ACh receptors on
neuromuscular junction
• s/s: eye lids drop, weak arm and
legs, voice change, swallowing
difficulty
 Toxins
 The potentially deadly botulinum toxin, produced by the bacteria
Clostridium botulinum, is selectively taken into cholinergic nerve endings
and cleaves the proteins needed for the exocytosis of the synaptic
vesicles
 This blocks nerve stimulation of the muscles producing a flaccid
paralysis
 Botulinum toxin is now used medically e.g relieve muscle spasms due to
excessive nerve stimulation
 Botox (a brand name for botulinum toxin)
 Causes local muscle paralysis
Cardiac Muscle
Structure of cardiac muscle
Cardiac muscles are made of cardiac muscle cells known as
cardiomyocytes
Cardiac muscles constitute the middle layer of cardiac walls (myocardium)
They are striated similar to skeletal muscles, though they differ in some
ways (see the comparison on upcoming next slides)
Structure of cardiac muscle

Pericardium
myocardium
endocardium
Structure of cardiac muscle
Central nucleus

Intercalated
disk

Branches
Structure of cardiac muscle

myofibrils
Myofibril

sarcomere

sarcomere sarcomere

Z-disks
Myofibril

thin filaments

myofibril

thick filaments
Myofibril

thin filaments
Actin

myofibril

thick filaments
myosin
Myofibril

A-band

myofibril

I-band H-zone I-band

Sarcomere

I- A-band Z-disk
band

myofibril
Sarcomere
Cross
bridges

myofibril
sarcomere

I- A-band Z-disk
band

myofibril
Thin myofilament
Troponin
complex
actin

Active sites
Tropomyosin
Structure of Cardiomyocyte
Cell membrane
Its is called sarcolemma, and forms a boundary between ICF and ECF.
At the Z-disks, sarcolemma invaginates deep into the cytoplasm to form
extensions known as T-tubules
T-tubules contain number of receptors including,
 voltage gated L-type calcium channel receptor,
 Sodium-Calcium exchangers,
 Calcium pumps
Structure of Cardiomyocyte
At the Z-disks, T-tubules and terminal cisternae of sarcoplasmic
reticulum runs close together to form pairs known as dyads (diads).
Dyads are important in intra-cellular calcium dynamics (as we’ll see
later)
Structure of Cardiomyocyte: Dyads
RyR receptor
T-tubule

Terminal
cistern L-type Ca
channel
Structure of Cardiomyocyte
Cardiac syncytium
Cardiomyocytes are branched cells and communicate with each other
via intercalated discs, forming cardiac syncytium.
Cardiac syncytium: is the group of muscle cells that join together and
act as a single unit (contract and relax together)
Cardiac syncytium

Intercalated discs
Structure of Cardiomyocyte
Intercalated discs
Are the structures that connect adjacent cardiac muscle cells
At the intercalated disc, two adjacent cells are connected via three
types of cell junctions:
1) Desmosomes
2) Fascia adherens junctions
3) Gap junctions
Properties of Cardiomyocyte
Auto Rhythmicity
In contrast to smooth muscles and skeletal muscles that depend on
neuronal motor input for initiation of contraction, cardiac muscles are
capable of self generating their own impulses for muscle contraction
Some cardiomyocytes are structurally modified (in terms of membrane
ion channels etc). This modification causes instability in their
membrane potentials (continuously changing) due to continuous influx
of ions (through many leaky channels) that leads to membrane
depolarization and generation of action potentials.
Properties of Cardiomyocyte
It has a different action potential wave pattern
In contrast to smooth muscles and skeletal muscles that has 4 phases
action potential wave, cardiac muscles has 5 phases action potential
wave.
This is a cardioprotective in sense that, it prolongs an action potential
so that muscle cells have a time to rest before second excitation from
the SAN
Properties of Cardiomyocyte
Excitation-contraction coupling
Is the process by which excitation of cardiac cells due to arrival of
action potential at the cells activates calcium dynamics leading to
myocytes contraction
It begins with arrival of action potential at the sarcolemma
Excitation-contraction coupling
Is the process by which excitation of cardiac cells due to arrival of
action potential at the cells activates calcium dynamics leading to
myocytes contraction
It begins with arrival of action potential at the sarcolemma
Excitation-contraction coupling
Arrival of action potential at the sarcolemma depolarizes the cardiac cell.
This causes activation and opening of voltage gated Na+ channels,
leading to influx of sodium inside the cell. Sodium influx creates wave of
an electric current (through AP spread) to the T-tubules where it causes
opening of L-type voltage gated calcium channels, so that extra-cellular
calcium rushes into the cell.
Influx of Ca into the cell activates Ryanodine receptors at the diad, that
allows more and more Sarcoplasmic Calcium ions to come out into the
cytoplasm of the cell. This event is called Calcium induced calcium
release.
Calcium induced calcium release leads to higher concentration of calcium
in the cytoplasm
Excitation-contraction coupling
Calcium in the cytoplasm binds to the troponin C on the actin, that
causes conformational changes of tropomyosin. Changes in
tropomyosin conformation leads to exposure of actin active binding
sites and allows myosin cross bridges to bind
After binding to the active site, myosin head undergoes conformational
changes (bending towards the tail) the event that generates a force
that pulls actin towards the centre of the sarcomere, hence shortening
of the sarcomere (contraction)
During this conformational change, ADP molecules previously attached
to the myosin head becomes released, supplying the required energy
for this event (conformational change and pulling force)
Excitation-contraction coupling
This new orientation exposes the myosin head ATP binding site, leading
to binding of ATP molecule to the head.
Binding of ATP molecule causes a decrease in affinity of myosin to the
actin active sites, and as a result, myosin head detaches from the actin
active sites.
The process of detachment is accompanied by breakdown of ATP
molecule into ADP and phosphate, the event that leads to restoration
of affinity of myosin head to the actin active site.
The myosin head then binds to the next active site while releasing a
phosphate group during the process, and the process repeats again and
again, pulling actin towards the centre of sarcomere (contraction)
Excitation-contraction coupling
An increase in intra-cellular calcium concentration in-activates
Ryanodine receptors and L-type receptors while activating membrane
Calcium ATPase pumps and SERCAs
Ca is then expelled out of the cell through Na-Ca exchangers and
calcium ATPAse pumps.
While inside the cell, activated SERCAs pump Ca back into the
sarcoplasmic reticulum.
Removal of Calcium from the ICF lead to restoration of tropomyosin
conformation and blockage of actin binding sites, the process that leads
to muscle relaxation.
In contrast to skeletal muscle:

• Cardiac muscle action potential has a plateau due to Ca2+ influx and
K+ efflux.
• Cardiac muscle contraction requires Ca2+ influx from ECF to induce
Ca2+ release from sarcoplasmic reticulum (Ca2+-induced Ca2+
release).
• Cardiac myocytes are electrically coupled to each other by gap
junctions.
Clinical implication
Arrhythmias:
It can be due to conductional causes, pacemaker dysfunction, abnormal
calcium dynamics or structural abnormalities (eg died muscle cells,
hypertrophic cardiomyopathies, dilated cardiomyopathies, restrictive
cardiomyopathies, mutations eg dysfunctional troponins)
Clinical implication
Arrhythmias:
Ryanodine receptors agonist: Caffeine binds to ryanodine receptors and
can induce spontaneous calcium release from sarcoplasmic reticulum
(can lead to hyperexcitable heart muscles and arrhythmias)
Also binding of caffeine to ryanodine receptors decreases intracellular
calcium threshold needed to open ryanodine receptors to cause
Calcium induced calcium release.
Clinical implication
Drugs:
Ryanodine receptors antagonist: Dantrolene blocks and stabilize
ryanodine receptors inhibiting spontaneous release of Ca2+ from
sarcoplasmic reticulum (eg: in arrhythmias associated with malignant
hyperthermia)
Cardiac vs Skeletal muscles
Similarities

Both are striated

Similar contraction mechanism

Both has T-tubules

Both has similar organelles required for
contraction
Cardiac vs Skeletal muscles
Cardiac Skeletal
Parallel close to each
Branched cell
other
Central nucleus Peripheral nuclei

Single nucleus/cell Multiple nucleus/cell

Involuntary Mainly voluntary
contraction contraction
Auto-rhythmicity Depends on motor input
Cardiac vs Skeletal muscles
Cardiac Skeletal
Doesn’t not fatigue Easily fatigue
Moderate contraction High/slow speed of
speed contraction
lesser SR Extensive SR
SR forms dyads with T- SR forms triads with T-
tubules tubules
T-tubules are found at T-tubules are found at the
the Z-disk A-I bands junction
Smooth Muscle
 SM structure

• Smooth muscle cells (SMC)

have a single nucleus.

• SMCs have thick, thin

filaments, and tropomyosin
but NO troponin.

• The thin filaments are

anchored either to the
plasma membrane or to
cytoplasmic structures known
as dense bodies.

• The filaments are not

arranged into myofibrils, NO
sarcomeres, NO banding
pattern. 64
 Introduction

• Smooth muscle cell is spindle-shaped, with a diameter

between 2 and 10 µm, and length ranging from 50 to
400 µm.

• They are much smaller than skeletal muscle fibers.

• Mostly are found in visceral organs like the walls of

Blood vessels, bronchioles, tubular digestive tract, the
ureters, the ductus differentia, the uterus etc.

65
 Comparison of smooth vs skeletal
muscle contraction
• The slow onset of contraction and prolonged
contraction - is caused by the slowness of cycling of the
cross-bridges with the actin filaments

• Low energy is required to sustain the same tension of

contraction in smooth muscle as in skeletal muscle.

• The maximum force of contraction of smooth muscle is

often greater than that of skeletal muscle.

• Latch Mechanism Facilitates Prolonged Holding of

Contractions of Smooth Muscle.
 Types of Smooth Muscle
Multi-unit smooth muscle
• Is composed of discrete, separate,
smooth muscle fibers.
• Innervated by a single nerve ending
• Each fiber can contract independently of
the others.
• The outer surfaces of these fibers care
covered by a thin layer of basement
membrane.
• Examples are the ciliary and the iris
muscle of the eye, and the piloerector
muscles that cause erection of the hairs
when stimulated by the sympathetic
nervous system.
67
 Types of Smooth Muscle
Unitary Smooth Muscle
• Is also called syncytial smooth muscle or
visceral smooth muscle.
• The term unitary does not mean single
muscle fiber.
• Means a mass of hundreds to thousands of
smooth muscle fibers that contract together
as a single unit.
• Cell membranes are joined by many gap
junctions through which Potentials, or ion
flow can travel from one fiber to the next and
cause the muscle fibers to contract together.
• Examples in gastrointestinal tract, bile ducts,
ureters, uterus, and many blood vessels.
Innervation of smooth muscles
 Smooth Muscle Contraction and its
Control
Cross-Bridge Activation:
• Cross-bridge cycling in smooth muscle is controlled by a
Ca2+regulated enzyme, myosin light chain kinase (MLCK)
that phosphorylates myosin.

• Only the phosphorylated form of smooth muscle myosin

can bind to actin and undergo cross-bridge cycling.

• To relax a contracted smooth muscle, myosin must be

dephosphorylated because dephosphorylated myosin is
unable to bind to actin.

• This dephosphorylation is mediated by the enzyme myosin

light-chain phosphatase (MLCP).
70
 Sources of Cytosolic Ca2+
• Two sources of Ca2+ contribute to
the rise in cytosolic Ca2+ that
initiates smooth muscle
contraction:
1. Extracellular Ca2+ entering the
cell through plasma-
membrane.
2. The sarcoplasmic reticulum

• To relax, the Ca2+ has to be

removed either to the SR or back
to the extracellular fluid.
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Smooth Muscle Contraction
Smooth muscle relaxation
Smooth Muscle Neuromuscular Junctions
• The autonomic nerve fibers that
generally branch diffusely on top of
a sheet of muscle fibers, without
making direct contact.
• It forms diffuse junctions and
contact junctions that secrete their
transmitter substance into the
matrix.
• Terminal axons have multiple
varicosities containing
neurotransmitters.
• Neurotransmitter can be excitatory
or inhibitory.
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