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Disorders of Skeletal, Cardiac and

Smooth muscle cells- Myasthenia


Gravis, Muscular Dystrophy and
Myotonia.

Dr. Karama Mankaga


Kenyunko
Group 11
Facilitator: Dr. M. Njelekela
Objectives
By the end of this session we should be
able to :
1.Describe different types of muscle cells
2.Differentiate between skeletal and
cardiac muscles
3.Differentiate between smooth and
other types of muscles
4.Describe pathophysiology of different
types of myopathies
Introduction
Body movement (Locomotion)
Maintenance of posture
Respiration
Diaphragm and intercostal contractions
Communication (Verbal and Facial)
Constriction of organs and vessels
Peristalsis of intestinal tract
Vasoconstriction of b.v. and other structures
(pupils)
Heart beat
Production of body heat (Thermogenesis)
Properties of Muscle
Excitability: capacity of muscle to
respond to a stimulus
Contractility: ability of a muscle to
shorten and generate pulling force
Extensibility: muscle can be
stretched back to its original length
Elasticity: ability of muscle to recoil
to original resting length after
stretched
Types of Muscle
Skeletal
Attached to bones
Makes up 40% of body weight
Responsible for locomotion, facial expressions, posture, respiratory
movements, other types of body movement
Voluntary in action; controlled by somatic motor neurons
Smooth
In the walls of hollow organs, blood vessels, eye, glands, uterus, skin
Some functions: propel urine, mix food in digestive tract,
dilating/constricting pupils, regulating blood flow,
In some locations, autorhythmic
Controlled involuntarily by endocrine and autonomic nervous
systems
Cardiac
Heart: major source of movement of blood
Autorhythmic
Controlled involuntarily by endocrine and autonomic nervous
systems
Sarcoplasmic Reticulum
(SR)

Figure 9.5
Cardiac Muscle
Found only in heart
Striated fibers that branch
Each cell usually has one nucleus
Fibers joined by intercalated disks
IDs are composites of desmosomes and gap junctions
Allow excitation in one fiber to spread quickly to
adjoining fibers
Under control of the ANS (involuntary) and
endocrine system (hormones)
Some cells are autorhythmic
Fibers spontaneously contract (aka Pacemaker cells)
Cardiac Muscle
Smooth Cells are not striated
Fibers smaller than those in
Muscle skeletal muscle
Spindle-shaped; single, central
nucleus
More actin than myosin
No sarcomeres
Not arranged as symmetrically
as in skeletal muscle, thus NO
striations.
Caveolae: indentations in
sarcolemma;
May act like T tubules
Dense bodies instead of Z disks
Have noncontractile intermediate
filaments
Smooth Muscle
Is innervated by autonomic nervous system
(ANS)
Visceral or unitary smooth muscle
Only a few muscle fibers innervated in each
group
Impulse spreads through gap junctions
Whole sheet contracts as a unit
Often autorhythmic
Multiunit:
Cells or groups of cells act as independent units
Arrector pili of skin and iris of eye
DIFFERENCES BETWEEN
CARDIAC AND SKELETAL
MUSCLES
STRUCTURAL
DIFFERENCES
The T tubules in a cardiac muscle cell are short
and broad, and there are no triads. The T tubules
encircle the sarcomeres at the Z lines rather than
at the zone of overlap.
The SR of a cardiac muscle cell lacks terminal
cisternae, and its tubules contact the cell
membrane as well as the T tubules .
Each cardiac muscle cell contact several others at
a specialized sites known as intercalated discs.
The sarcoplasm of cardiac muscle cells contain
large number of mitochondria because they are
almost dependent on aerobic metabolism for
energy production
FUNCTIONAL
DIFFERENCES
Cardiac muscle tissue contracts without neural
stimulation (automaticity).

Cardiac muscle cells do not produce tetanic


contraction like in skeletal muscle, this is an
important phenomenon because a heart in a
sustained tetanic contraction could not pump
blood.

cardiac muscle contraction last roughly 10


times longer than those in skeletal muscle cells.
DIFFERENCES BETWEEN SMOOTH
MUSCLE TISSUE AND OTHER
MUSCLE TISSUES
STRUCTURAL DIFF:
A smooth muscle fiber has no T tubules,
and the sarcoplasmic reticulum forms a
loose network throughout the sarcoplasm.
Smooth muscle tissues are nonstriated.
Thick filaments are scattered throughout
the sarcoplasm of a smooth muscle cell.
The myosin of smooth muscle cells have
more cross-bridges per thick filament .
DIFFERENCES BETWEEN SMOOTH
MUSCLE TISSUE AND OTHER
MUSCLE TISSUES
Dense bodies are not arranged in
straight lines, so when a contraction
occurs, the muscle cell twists like a
corkscrew.
Although smooth muscle cells are
surrounded by connective tissue, the
collagen fibers never unite to form
tendons or aponeuroses as they do in
skeletal muscles.
FUNCTIONAL DIFF

ExcitationContraction Coupling
The calcium released after trigger for
smooth muscle contraction is
interacting with calmodulin, a
calcium-binding protein.
Calmodulin then activates the
enzyme myosin light chain kinase,
which breaks down ATP and initiates
the contraction.
FUNCTIONAL DIFF

Control of Contractions Many smooth muscle


cells are not innervated by motor neurons, their
nerves are derived from the autonomic division of
nervous system
Thus smooth muscles are not normally under
voluntary control.
Multiunit smooth muscle cells are innervated in
motor units comparable to those of skeletal
muscles, but each smooth muscle cell may be
connected to several motor neurons rather than to
just one.
In contrast, many visceral smooth muscle cells
lack a direct contact with any motor neuron.
FUNCTIONAL DIFF

LengthTension Relationships A stretched


smooth muscle soon adapts to its new length
and retains the ability to contract on demand
(plasticity.)
Smooth muscle can contract over a range of
lengths four times greater than that of skeletal
muscle.
This ability is especially important for digestive
organs that undergo great changes in volume,
such as the stomach.
Like skeletal muscle fibers, smooth muscle cells
often undergo sustained tetanic contractions.
Structure of Actin and
Myosin
Sliding Filament Model of
Contraction
Thin filaments slide past the thick
ones so that the actin and myosin
filaments overlap to a greater degree
In the relaxed state, thin and thick
filaments overlap only slightly
Upon stimulation, myosin heads bind
to actin and sliding begins
Sliding Filament Model of
Contraction

Each myosin head binds and detaches


several times during contraction,
acting like a ratchet to generate
tension and propel the thin filaments
to the center of the sarcomere
As this event occurs throughout the
sarcomeres, the muscle shortens
Excitation contration
coupling
Excitation-contraction (EC) coupling is
a term used to describe the
physiological process of converting an
electrical stimulus to a mechanical
response .
An action potential arrives to
depolarize the cell membrane.
This depolarization results in an
increase in cytosolic calcium that is
called a calcium transient.
Excitation contration
coupling...
Released Ca binds to troponin on the thin
filaments causing tropomyosin to move
away from its blocking position uncovering
cross-bridge binding sites on actin.
Myosin cross-bridges bind to actin.
Cross bridge cycle produces tension and
shortening.
Cycles of cross-bridges movement continue
as long as Ca ion remains bound to troponin
Excitation contration
coupling...
Cytocolic Ca concentation decreases
as Ca is actively transported into
sarcoplasmic reticullum by Ca-
ATPase.
Removal of Ca from troponin restores
blocking action of tropomyosin, the
cross-bridges ceases and the muscle
fiber relaxes
Contraction Mechanism
Muscle Tissues Disorders
Myasthenia Gravis
Myasthenia Gravis: is a neuromuscular
disorder characterized by weakness and
fatigability of skeletal muscles.
The underlying defect is a decrease in
the number of available acetylcholine
receptors (AChRs) at neuromuscular
junctions due to an antibody-mediated
autoimmune attack.
Pathophysiology
In MG, the defect is a decrease in the number
of available AChRs at the postsynaptic
muscle membrane.
These changes result in decreased efficiency
of neuromuscular transmission.
Therefore, although ACh is released normally,
it produces small end-plate potentials that
may fail to trigger muscle action potentials.
Failure of transmission at many
neuromuscular junctions results in weakness
of muscle contraction.
Pathophysiology .....
The neuromuscular abnormalities in MG
are brought about by an autoimmune
response mediated by specific anti-AChR
antibodies.
It is believed that, the thymus plays a role
in this process.
The thymus is abnormal in ~75% of
patients with MG; in ~65% the thymus is
"hyperplastic,. An additional 10% of
patients have thymic tumors (thymomas).
Pathophysiology....
Muscle-like cells within the thymus
(myoid cells), which bear AChRs on
their surface, may serve as a source
of autoantigen and trigger the
autoimmune reaction within the
thymus gland
Pathophysiology .....
The anti-AChR antibodies reduce the number of
available AChRs at neuromuscular junctions by
three distinct mechanisms:
(1) accelerated turnover of AChRs by a
mechanism involving cross-linking and rapid
endocytosis of the receptors;
(2) blockade of the active site of the AChR, i.e.,
the site that normally binds ACh; and
(3) damage to the postsynaptic muscle membrane
by the antibody in collaboration with
complement.
Pathophysiology....
An immune response to muscle-
specific kinase (MuSK) can also result
in myasthenia gravis,
The pathogenic antibodies are IgG
and are T cell dependent. Thus,
immunotherapeutic strategies
directed against T cells are effective
in this antibody-mediated disease.
DIAGNOSTIC PROCEDURE

1. Pharmacological testing : Edrophonium


chloride (tensilon) test
2. Serological testing : Antibody against
AChR
3. Electrophysiological testing : RNST,
SFEMG
4. Other : ocular cooling
Muscular Dystrophy
(MD)
Muscular Dystrophy: group of genetic
disorders that are characterized by
progressive loss of muscle integrity, wasting,
and weakness.
It is due to disorders involving dystrophin,
which is the gene responsible in making
protein for healthy muscle.
Dystrophin-Associated Protein (DAP)
Complex composed of the extracellular,
transmembrane, and intracellular
components
Pathophysiology
Normal skeletal muscle tissue contains only
small amounts of dystrophin (about 0.002% of
total muscle protein),
Its absence or abnormal expression leads to
the development of a severe and currently
incurable constellation of symptoms.
Most readily characterized by several aberrant
intracellular signaling pathways that ultimately
yield pronounced myofiber necrosis as well as
progressive muscle weakness and fatigability.
Major Classifications

There are eight major classifications of


muscular dystrophy.
Each classification differs by the extent
and distribution of muscle weakness,
age of onset, rate of progression,
severity of symptoms, and family history
(including any pattern of inheritance)
Classifications
1. Duchenne MD
2. Becker MD
3. Facioscapulohumeral MD
4. Myotonic MD
5. Emery-Dreifuss MD
6. Distal/Limb-girdle MD
7. Congenital MD
8. Oculopharyngeal MD
Duchenne MD and Becker MD are the
muscular disorders which are most
common and severe dystrophies.
Most DMD patients become
wheelchair-dependent early in life, and
the gradual development of cardiac
hypertrophya result of severe
myocardial fibrosistypically results in
premature death in the first two or
three decades of life.
Myotonia
Myotonia is a symptom of a of certain
neuromuscular disorders characterized by the
slow relaxation of the muscles after voluntary
contraction or electrical stimulation.
Generally, repeated effort is needed to relax
the muscles, and the condition improves after
the muscles have warmed-up.
Individuals with the disorder may have trouble
releasing their grip on objects or may have
difficulty rising from a sitting position and a
stiff, awkward gait.
Myotonia...
Myotonia is a symptom commonly
seen in patients with myotonic
muscular dystrophy, a group of
disorders called channelopathies , such
as Myotonia Congenita (Congenital
Myotonia) of which two types called
Becker's Disease(Autosomal recessive)
and Thomsen's Disease(Autosomal
dorminant) exist.
Pathophysiology
Myotonia congenital can be acquired
or inheritated condition, can be
autosomal dorminant or an
autosomal recessive.
It is caused by an abnormality in the
muscle membrane.
Specifically, the ion channels that
control the contraction of muscle
fibers.
Pathophysiology...
Myosin is defective in myotonia.
Both conditions are caused by mutation of
CLCN1, the gene encoding CLC-1 protein
leading to the alteration of the gating
properties and dramatic change in ion
selectivity.
CLC-1 is the chloride channel of the
skeletal muscle
Treatment
mexiletine, which is able to reduce
myotonia with doses of 200 mg two
or three times a day.
Phenytoin 200300 mg per day can
also be used to treat myotonia.
References
1. Guyton & Hall; Textbook of Medical
Physiology 11th Edition
2. Harrisons Principle of Internal
Medicine 17th Edition
3. William F. Ganong; Review of
Medical Physiology 21st Edition
4. Journal of Neuromuscular disorders
2009