neuro-muscular junction and skeletal muscular contraction dr.rahul

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NEURO-MUSCULAR JUNCTION & MECHANISM OF SKELETAL MUSCLE CONTRACTION by Dr. Rahul M.D.Final year (Physiology) ,SMS Medical College Jaipur

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Page 1: NEURO-MUSCULAR Junction and  SKELETAL muscular contraction DR.RAHUL

NEURO-MUSCULAR JUNCTION & MECHANISM OF SKELETAL

MUSCLE CONTRACTION

by Dr. Rahul M.D.Final year (Physiology) ,SMS Medical

College Jaipur

Page 2: NEURO-MUSCULAR Junction and  SKELETAL muscular contraction DR.RAHUL

FIGURE 6–13 The neuromuscular junction. (a) Scanning electronmicrograph showing branching of motor axons with terminals embedded in grooves in the muscle fiber’s surface. (b) Structure of a neuromuscular junction. (From Widmaier EP, Raff H, Strang KT: Vanders Human Physiology.McGraw-Hill, 2008.)

We begin with Neuromuscular Junction

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The neuromuscular junction is the synapse

between a motor neuron and a skeletal muscle cell.

At the endplate, the motor neuron axon

arborizes into numerous terminal boutons that

contain large numbers of ACh-filled vesicles.

ACh is synthesized in the boutons from choline

and acetyl coenzyme A by choline

acetyltransferase.

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ACh then is pumped into the vesicles by a

specific ACh-H+ exchanger.

The basal lamina between the presynaptic and

postsynaptic membranes contains a high

concentration of the degradative enzyme AChE.

Case files Physiology: EUGENE C.TOY :LangeMc Graw Hills:2nded: 42-44

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SYNTHESIS OF Acetyl choline

Ach H+ exchanger

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Acetyl choline is synthesized within the mitochondria

from Choline in presence of choline acetyltransferase.

The storage vesicles and choline acetyltransferase are

produced in the soma and are transported to the axon

terminals.

The rate-limiting step in ACh synthesis in the nerve

terminals is the availability of choline, of which specialized

mechanisms ensure a continuous supply

(Medical physiology principles of clinical medicine :Rhodney A Rhoades : Lippincott : 4rth ed : chap3: pg 55)

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(Source:Ganong’s Medical Physiolog /TMH /24thed/Fig 5-7pg 104)

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(Source: Ganong’s Medical Physiolog /TMH /24thed/chap 6 /122)

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They involve the v-snare protein synaptobrevin in the

vesicle membrane locking with the t-snare protein

syntaxin in the cell membrane; a multiprotein complex

regulated by small GTPases such as rab3 is also

involved in the process.

Source:Ganong’s Medical Physiology /TMH /24thed/chap6/pg 121

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Several toxins which block neurotransmitter release

are zinc endopeptidases that cleave and hence

inactivate proteins in the fusion–exocytosis complex.

Tetanus toxin and botulinum toxins B, D, F, and G

act on synaptobrevin

Botulinum toxin C acts on syntaxin

Botulinum toxins A and B act on SNAP-25.

Clinical implications :

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Clinically, tetanus toxin causes spastic paralysis by

blocking presynaptic transmitter release in the CNS.

Botulism causes flaccid paralysis by blocking the

release of acetylcholine at the neuromuscular junction.

Source: Ganong’s Medical Physiology /TMH /24thed/chap6/pg 123

local injection of small doses of botulinum toxin

(botox) is efficacious in the treatment of various

conditions like Lower esophageal sphincter to relieve

achalasia and injection into facial muscles to remove

wrinkles

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?A 18-year-old college woman comes to the student

health service complaining of progressive

weakness.

She reports that occasionally her eyelids “droop”

she tires easily, even when completing ordinary

daily tasks such as brushing her hair.

She has fallen several times while climbing a flight

of stairs.

These symptoms improve with rest.

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Treated with the drug pyridostigmine.

After treatment, she reports a return of muscle

strength

The physician orders blood studies, which reveal

elevated levels of antibodies to ACh receptors.

Nerve stimulation studies show decreased

responsiveness of skeletal muscle on repeated

stimulation of motor neurons. The woman is diagnosed with Myasthenia Gravis

(Source: Physiology : Linda Costanzo/Elsevier/ 5th ed/pg.28)

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Myasthenia Gravis

Though ,release of Ach remains normal, but

reduction in the number of receptors, the EPP is

reduced and may fail to reach threshold for muscle

action

Antibodies are produced to ACh receptors on the

motor end plates of skeletal muscle that block ACh

receptors.

Autoimmune form of the neuromuscular disease.

Common in females, with peak incidence at 20 to 30

years of age.

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Thus , more normal EPP in the muscle fiber can be

produced even though many of the ACh receptors

are blocked by antibodies.

Muscle weakness and fatigability ensue.

AChE on the motor end plate normally degrades ACh

By inhibiting the AChE with pyridostigmine, ACh

levels in the neuromuscular junction are

maintained at a high level prolonging the time

available for ACh to activate its receptors on the

motor end plate.

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Lambert–Eaton Syndrome

Muscle weakness is caused by an autoimmune attack

against one of the Ca2+ channels in the nerve endings at

the neuromuscular junction.

This decreases the normal Ca2+ influx that causes

acetylcholine release.

Proximal muscles of the lower extremities are

primarily affected, producing a waddling gait and

difficulty raising the arms.(Source:Ganong’s Medical Physiolog /TMH /24thed/Fig 5-7pg 104)

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venom of black widow spider exerts its effect by

triggering explosive release of Ach from the storage

vesicles, not only at N.M junction but all cholinergic

sites. All cholinergic sites undergoes prolong

depolarization.

Agents that alters the function of N.M junction

Black widow spider venom :

Page 22: NEURO-MUSCULAR Junction and  SKELETAL muscular contraction DR.RAHUL

Source: Human Physiology: Vander et al: The Mechanism of Body Function McGraw−Hill Companies 2001/8th Ed : Chap:11: Pg 307

Curare

competitively binds to ACh receptors not allowing

Ach to bind so no opening of ion channels

curare not destroyed by acetylcholinesterase.

Though motor nerves conducting normal action

potentials and release ACh, there is no EPP in the

motor end plate and hence muscles paralysis.

curare poisoning leads to death by asphyxiation

Used as arrowhead poison

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(Source: Physiology : Linda Costanzo/Elsevier/ 5th ed/pg.34 )

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Source: Human Physiology: Vander et al: The Mechanism of Body Function McGraw−Hill Companies 2001/8th Ed Chap:11 : Pg :297

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Titin is a prominent target for mutations that give

rise to muscle disease .

Mutations that encodes for shorter titin stucture

have been associated with Dilated Cardiomyopathy.

Skeletal muscle associated Tibialis muscular

dystrophy is a genetic muscle disease of titin .

Source: Ganong’s Medical Physiology /TMH /24thed/chap5/pg 100

Clinical Pearls

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The process by which depolarization of the

muscle fiber initiates contraction is called

excitation–contraction coupling.

The action potential is transmitted to all the fibrils

in the fiber via the T system.

It triggers the release of Ca 2+ from the terminal

cisterns, the lateral sacs of the sarcoplasmic

reticulum next to the T system.

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Page 32: NEURO-MUSCULAR Junction and  SKELETAL muscular contraction DR.RAHUL

Depolarization of the T tubule membrane activates the

sarcoplasmic reticulum via dihydropyridine receptors

(DHPR), named for the drug dihydropyridine, which blocks

them .

DHPR are voltage-gated Ca2+channels in the T tubule

membrane.

In cardiac muscle, influx of Ca2+via these channels

triggers the release of Ca2+stored in the sarcoplasmic

reticulum (calcium induced calcium release) by activating the

ryanodine receptor (RyR).

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RyR is named after plant alkaloid ryanodine . It is a

ligand-gated Ca2+channel with Ca 2+as its natural

ligand.

In skeletal muscle, Ca 2+entry from ECF by this

route is not required for Ca 2+release.

DHPR serves as voltage sensor ,unlocks release

of Ca 2+ from the nearby sarcoplasmic reticulum via

physical interaction with the RyR.

Page 34: NEURO-MUSCULAR Junction and  SKELETAL muscular contraction DR.RAHUL

Terminal cisternae (Lateral sacs)contains a protein,

calsequestrin, that weakly binds calcium, storing

calcium in bound form maintaining a low free calcium

concentration in the sarcoplasmic reticulum.thereby

reducing the work of Ca ATPase pump.

Ca 2+is reduced in the muscle cell by the

sarcoplasmic or endoplasmic reticulum Ca2+

ATPase (SERCA) pump.

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SERCA pump uses energy from ATP hydrolysis to remove

Ca2+ from the cytosol back into the terminal cisterns, where

it is stored until released by the next action potential.

Ca2+concentration outside the reticulum when lowered

sufficiently, chemical interaction between myosin and actin

ceases and the muscle relaxes.

ATP provides the energy for both contraction (at the

myosin head) and relaxation (via SERCA) .

Source:Ganong’s Medical Physiology /TMH /24thed/chap5/pg 103

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Traced due to a mutation in RyR ( the Ca2+

release channel in the sarcoplasmic reticulum).

The mutation results in an inefficient feedback

mechanism to shut down Ca 2+ release after

stimulation of the RyR.

Malignant hyperthermia :

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Anaesthetic agents like Halothane,exposure to

high enviornmental heat and strenous excercise

triggers abnormal release of ca2+ from

sarcoplasmic reticulum in muscle cell resulting in

sustained muscle contraction and heat generation

Source: Ganong’s Medical Physiology /TMH /24thed/chap5/pg 105

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Interaction Between the “Activated” Actin Filament and the Myosin Cross-Bridges—The “Walk-Along” Theory(Ratchet Theory) OR Sliding Filament Theory of Contraction.

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Discharge of motor neuron

Release of transmitter (Ach) at motor end-plate

Binding of Ach to nicotinic Ach receptors

Increased Na+ and K+ conductance in end-plate membrane

Generation of end- plate potential

Generation of action potential in muscle fibers

Inward spread of depolarization along T tubules

Release of Ca2+ from terminal cisterns of sarcoplasmic reticulum and diffusion to thick and thin filaments

Binding of Ca2+ to troponinC, uncovering myosin-binding sites on actin

Formation of cross-linkages between actin and myosin and sliding of thin on thick filaments, producing movement

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Cessation of interaction between actin and myosin

Ca2+ pumped back into sarcoplasmic reticulum

Release of Ca2+ from troponin

steps of relaxation

(Source: Ganong’s Medical Physiolog /TMH /24thed/Fig 5-7pg 104)

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A single action potential results in the release of a

fixed amount of Ca2+ from the sarcoplasmic reticulum,

which produces a single twitch.

The twitch is terminated (relaxation occurs) when

the sarcoplasmic reticulum reaccumulates this Ca2+.

However, if the muscle is stimulated repeatedly,

there is insufficient time for the sarcoplasmic

reticulum to reaccumulate Ca2+, and the intracellular

Ca2+concentration never returns to the low levels

that exist during relaxation.

MECHANISM OF TETANUS

(Source: Physiology : Linda Costanzo/Elsevier/ 5th ed/pg.38)

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Source: HumanPhysiology: Vander et al: The Mechanism of Body Function McGraw−Hill Companies 2001/8th Ed : chap:11: Pg :313

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