CME anaesthesia

1. Dr Mohamed Asri Bin Mohamed
Zaini
Neuromuscular Junction and
Muscle Contraction Physiology

2. Know and describe the followings:
The physiology and anatomy of the skeletal muscle and NM junction.
The general mechanism of skeletal muscle contraction.
Motor End Plate potential and how action potential and excitation-contraction coupling are generated in
skeletal muscle.
The molecular mechanism of skeletal muscle contraction & relaxation.
Sliding filament mechanism.
Drugs/ diseases affecting the neuromuscular transmission.
Objectives
At the end of the CME MOs should be able to:

3. Chemical Signals
 One neuron will transmit info to another neuron or to a muscle
or gland cell by releasing chemicals called neurotransmitters.
 The site of this chemical interplay is known as the synapse.
 An axon terminal (synaptic knob) will adjoin with another cell, a neuron,
muscle fiber, or gland cell.
 This is the site of transduction – the conversion of an electrical signal into
a chemical signal.

4. Neuromuscular Junction (NMJ)

5. Anatomy of the Neuromuscular Junction
• Motor End Plate
• Synaptic trough/
gutter
• Presynaptic
terminal
• Postsynaptic
terminal
• Synaptic
space/cleft
• Subneural cleft
• Acetylcholine (Ach)
• Synaptic vesicles

6. Acetylcholine
 Ach is synthesized locally in the
cytoplasm of the nerve terminal ,
from active acetate
(acetylcoenzyme A) and choline.
 Then it is rapidly absorbed into
the synaptic vesicles and
stored there.
 The synaptic vesicles themselves
are made by the Golgi Apparatus
in the nerve cell-body.
 Then they are carried by
Axoplasmic Transport to the nerve
terminal , which contains around
300,000 vesicles .
 Each vesicle is then filled with
around 10,000 Ach molecules .

7.  Ach combines with its receptors
in the subneural clefts. This opens
sodium channels  & sodium
diffuses into the muscle causing a
local,non-propagated potential
called the “ End-Plate Potential
(EPP)”,.
 This EPP triggers a muscle AP
which spreads down inside the
muscle to make it contract .

9. 1425 – 2004
Destruction of Ach

10. Physiology of Skeletal Muscle
Contraction

11. The Muscle Action Potential (AP)
 Muscle Resting Membrane Potential = -90 mV (
same as in nerves ) .
 Duration of AP = 1-5 ms ( longer duration than
nerve AP , which is usually about 1 ms ) .
 Conduction Velocity = 3-5 m/s ( slower than big
nerves ) .

12. Skeletal Action Potential

13.  Each muscle cell (fiber)
is covered by a cell-
membrane called
Sarcolemma, or
myolemma or
plasmalemma.
 double-layered
membrane inside the
endomysium
 Each cell contains
between a few hundreds
to a few thousands
Myofibrils.

14.  Each Myofibril contains Actin filaments (thin) & Myosin
(thick) filaments .
 Each myofibril is striated: consisting of dark bands
(called A-bands) and
light (I-bands).

15. Sarcoplasm=
matrix inside muscle fiber in which myofilaments
suspended
-a cytoplasma of muscle fibre containing ATPs and
Phosphagens
Sarcoplasmic reticulum=
it is endoplasmic reticulum inside sarcoplasm full of
Ca.
Transverse- tubules(T-tubules):-
extend from one side of muscle to other
-permit rapid transmission of AP into the cell

16. Sarcomere=
contractile unit of muscle, it is the zone between
two Z lines ( discs)=2 micrometer in length in
resting state.
Z discs (lines) = lines extend all way across
myofibrils

17. Inside each sarcomere there are 3 bands:-
I band = of actin only
-
- H band= of myosin only
- A band= formed of actin & myosin
filaments

19. The functional unit of a myofibril is the Sarcomere

20.  The EPP at the motor end-
plate triggers a muscle AP
 The muscle AP spreads
down inside the muscle
through the Transverse
Tubules ( T-tubules )
to reach the Sarcoplasmic
Reticulum (SR) .
 In the SR the muscle AP
opens calcium channels
( in the walls of the SR) 
calcium passively flows out (
by concentration gradient )
of the SR into muscle
cytoplasm Ca++ combines
with Troponin

21. > Each G-Actin molecule has a binding site for Myosin head
( called actin active sites )
> These active sites are covered and hidden from the Myosin head by the
inhibitory protein Tropomyosin
> When Troponin is activated by Ca++ it will move the Tropomyosin away
from these sites and expose them for Myosin.
> then myosin immediately gets attached to them .
> when the myosin head attaches to actin it forms a “ cross-bridge”

22. 
Each Myosin molecule has (1) Head (2) Hinge (joint ) and ( 3 )
Tail ; and each myosin head contains an ATP binding site as
well as ATP-ase enzyme .

23. Myosin (2)

Each 200 myosin molecules aggregate to form a
myosin filament , from the sides of which project
myosin heads in all directions .

24. 
The activated troponin pulls the inhibitory protein
tropomyosin away from the myosin binding sites on actin
 and once these sites on Actin are exposed ( uncovered )
 myosin heads quickly bind to them

25. This binding activates the enzyme ATPase in the Myosin Head 
it breaks down ATP releasing energy  which is used in the
“Power Stroke ” to move the myosin head

26. The “ power stroke ” means tilting of the cross-bridge head
( myosin head ) and dragging ( pulling ) of actin filament

27.  When contraction takes
place Actin & Myosin slide
upon each other , & the
distance between two z-
discs decreases : This is
called
Sliding Filament Mechanism

28. MOLECULAR MECHANISM OF
MUSCLE CONTRACTION
Excitation –contraction coupling

31. Sliding Filaments

33. Drugs That Stimulate the Muscle Fiber by Ach-Like Action:
 Methacholine, Carbachol, and Nicotine.
They act for minutes or hours—are not destructed by cholinesterase.
Drugs That Stimulate the NMJ by Inactivating Acetylcholinesterase:
 Neostigmine, Physostigmine [inactivate acetylcholinesterase for several hours]
 Diisopropyl fluorophosphate (nerve gas poison) [inactivates acetylcholinesterase for weeks -------can
cause death because of respiratory muscle spasm]
Drugs That Enhance or Block
Transmission at the
Neuromuscular Junction

34. Drugs That Block Transmission at the NMJ
 Curare & Curariform like-drugs.
Prevent passage of impulses from the nerve ending into the muscle by blocking
the action of Ach on its receptors.
act by competitive inhibition to Ach at its receptors & can not cause
Depolarization.
 Botulinum Toxin.
Bacterial poison that decreases the quantity of Ach release by the nerve terminals.
Drugs That Enhance or Block
Transmission at the
Neuromuscular Junction

35. Myasthenia Gravis
 Auto-immune disease
 Antibodies against Ach receptors destroy many of the
receptors  decreasing the EPP , or even preventing its
formation  weakness or paralysis of muscles
( depending on the severity of the disease ) .
  patient may die because of paralysis of respiratory
muscles.
 Treatment : Anti-cholinestersae drugs . These drugs
inactivate the cholinesterase enzyme ( which destroys
Ach) and thereby allow relatively large amounts of Ach
to accumulate and act on the remaining healthy
receptors  good EPP is formed  muscle contraction .

36. Myasthenia Gravis
 affects eyelid, extra ocular
bulbar and proximal limb
muscles.
 Presents with ptosis,
dysarthria, dysphagia, and
proximal limb weakness in
hands& feet.

37. Summary
Muscle contraction physiology is a complex process that involves the interaction of muscle fibers, nervous system signals, and
various cellular mechanisms.
Here's an overview of how muscle contraction occurs:
1. Nervous System Stimulation
2. Generation of Action Potential
3. Arrival at Neuromuscular Junction
4. Release of Acetylcholine (ACh)
5. Muscle Fiber Activation
6. Muscle Action Potential
7. Release of Calcium (Ca2+)
8. Cross-Bridge Formation
9. Sliding Filament Theory
10. Muscle Contraction
11. Termination of Signal
12. Muscle Relaxation
Disorders of Neuromuscular Junctions
1. Myasthenia Gravis
2. Lambert–Eaton Myasthenic Syndrome

38. Thanks