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DENERVATION AND DISUSE, FEBRUARY 8, 2006
Denervation__________________________________________________________
Changes in Motor Axons and Neuromuscular Junctions
I.
Distal Stump
 Following nerve section or nerve crush, the distal nerve stump remains
capable of propagating action potentials for many hours, in humans this
may persist for up to 200hr.
 Wallerian degeneration: The process of degeneration when the axon
commences to break up
1.
Retraction of myelin
2.
Axon cylinder – disruption of the microtubules,
endoplasmic reticulum and neurofilaments
3.
Myelin sheath now begins to break up.
4.
Schwann cell first spread over the denuded nodes of
ranvier and then undergo mitotic division.
5.
Macrophages appear
6.
Nerve fibers atrophy and many appear collapsed after
distal nerve section.
Fig. 1 Summary of Wallerian Degeneration
II.
Neuromuscular junction
 The first degenerative changes seen after an axon has been divided are
at the neuromuscular junction.
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The onset of changes in the axon terminal depends on two things: the
length of the distal stump of axon and the species of animal
 The onset of end-plate failure is also species dependent, being much
later larger mammals.
 When degenerative changes have started, only 3-5 hours are required for
complete disruption of the endplate, which is accomplished by clumping
of synaptic vesicles, swelling of mitochondria, breaking up of cristae,
glycogen bags appear in the axoplasm, and lysosomes become evident.
 There is a latent period of spontaneous discharge and electrical
stimulation of the axon results in normal neuromuscular transmission,
after this period the neuromuscular function fails abruptly.
 Silent synapses: neuromuscular junctions that are largely intact, but in
which there is insufficient depolarization of the muscle fiber membranes
to generate action potentials.
Changes in Muscle Fibers
Denervation atrophy – gradual wasting of muscle after a nerve to the muscle is
severed, demonstrates that the muscle fibers are dependent upon the motoneuron
for maintenance of their normal structure
I.
Atrophy
 Atrophy can be detected at about the 3rd day of denervation and is rapid
during the ensuing 2 months
 Denervation affects both red and white fibers equally.
 Atrophy is the result of increased protein degradation and decreased
protein synthesis
II.
Myonuclei
 As early as the 2nd day after denervation, myonuclei become rounded, instead
of narrow and elongated and the nucleoli become enlarged and more
prominent
 Many nuclei move into the centers of the fibers where they line up to form
chains.
 In late atrophy, all that remains of some fibers are chains or clumps of nuclei
surrounded by thin cylinders of cytoplasm.
III.
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Necrosis
May result in the death of a fiber, and can be restricted to part of a fiber.
Affected fibers swell, nuclei enlarge, and then fragment
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Vacuoles appear in cytoplasm, cross-striations become less distinct,
plasmalemma thickens
Mononuclear cells appear at the site of necrosis and subject the accumulating
fiber debris to phagocytosis.
Has been suggested that in long-term denervation, cycles of regeneration and
necrosis occur
Changes in the muscle ultrastructure
Atrophy begins at the periphery of the myofibril, but after 1 month
degeneration becomes visible in the interior
During the 1st week, mitochondria in both red and white fibers enlarge in the
longitudinal axis of the fiber; subsequently they shrink and form clusters,
some undergoing degeneration
Sarcoplasmic reticulum at first enlarges and then diminishes, although less
than the fiber itself
Other changes: abnormalities of the Z-disc, irregularities and small papillary
projections of the plasmalemma, focal dilatations of the transverse and
sarcoplasmic tubules
Enzyme activities
Rapid decrease in enzyme activities specific for fiber type, thus fiber type can
no longer be distinguished, i.e. red fibers become paler
Reductions in the activities of creatine kinase, several glycolytic enzymes and
two enzymes of the citric acid cycle
Twitch
Tensions developed during a single twitch or during a tetanus are reduced
Twitch become significantly slower, in both fast- and slow-twitch muscles,
although the twitches of the fast muscles remain considerably faster than those
of slow muscles
Changes in the Electrical Properties of muscle
1.
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Fall in resting membrane potential
Permeability of the fiber is altered
Muscle action potential has a lower rate of rise and a longer duration.
Sensitivity of the muscle fiber to ACh begins to spread out to involve the
remainder of the fiber.
Fibrillation potentials develop
Cholinesterase concentration in the endplate falls
Fast-twitch muscles become sensitive to caffeine
Denervated muscle fiber stimulates sprouting
Fig. 2 Summary of the Effects of denervation
Clinical Relevance
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Guillain-Barre Syndrome (GBS)
Amyotrophic Lateral Sclerosis
Post-polio syndrome
Disuse______________________________________________________________
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Effects of disuse are more marked in animals than in humans and are opposite
those induced by training.
Absence of load bearing is the most importance and/or influential factor
Slow-twitch fibers are more susceptible to disuse than fast-twitch fibers (in
animals)
Reduced fiber size is not the only change
Motor innervation may also be affected
Disused muscle is more fatigable
Effects of disuse are reversible.
Muscle wasting: becomes apparent after as little as 3 to 4 days bed rest.
 Amount of atrophy will depend on the usage of the muscles prior to
immobilization and thus is always greater in antigravity muscles, e.g. quadriceps,
compared to their antagonists, e.g. hamstrings.
 The length of the muscle at time of immobilization is critical, because of
sarcomere resorption.
 Estimates of muscle belly shrinkage may underestimate fiber atrophy if there is an
increase in connective tissue.
Fiber type specific muscle wasting
 Whether fast- or slow-twitch fibers preferentially atrophy is controversial. Results
are conflicting and probably depend on the choice of muscle, its degree of
previous usage, and the amount of isometric muscle contraction that takes place
within the cast.
 If only a small amount of isometric contraction is allowed, this will better
maintain the fast-twitch fibers, which are normally used intermittently, than the
more constantly employed slow-twitch fibers.
 Some studies have shown preferential slow-twitch fiber atrophy, and a decreased
percentage of slow-twitch fibers, as well as an increase in the fast-twitch type IIB
fibers. These results should be interpreted cautiously, as there is large fiber type
sampling inherent with the needle biopsy technique.
Motor unit recruitment
 There is a large decrease in voluntary strength after a period of disuse. This
decrease is due to an inability to recruit the motor unit population fully – an
example of the nervous system ‘forgetting’ a motor task
Animal models of disuse (cat and rat)
I.
Spinal cord isolation
II.
Local anesthetic or tetradotoxin
III.
Neurapraxia (pressure block of impulse conduction)
IV.
Neurotoxins
V.
VI.
Tenotomy and joint fixation
Animal models and fatigability
Disuse and the neuromuscular junction
 As few as 5 days immobilization results in motor axon terminal sprouting and
distortion in their longitudinal axes.
 Exposure of the synaptic folds and disruption of nerve terminals of both type I
and type II fibers
 Presence of several small axons over the same primary cleft which suggests that
some nerve terminals may also be regenerating
Length of Immobilized muscle
 If muscles are fixed in a shortened position, sarcomeres are removed, while
lengthening the muscle causes sarcomeres to be added. This addition/removal has
been shown to take place at the ends of the fibers.
 The stiffness of a limb, after removal from a cast, is due to the shortening of the
muscle fibers, as well as to changes in the joint capsules and ligaments. As the
shortened muscle is stretched, damage will occur to the myofilaments; however,
the end result of stretching is myofibrillar protein synthesis and the eventual
restoration of the missing sarcomeres.
Gene expression
 New proteins may be produces in the muscle fibers as a result of disuse, thus gene
expression must be modified, either at the transcriptional or translational levels,
e.g., lengthened soleus has increased IIB myosin heavy chain gene expression
 Passive stretch has been linked to gene expression, larger proteins in the muscle
fiber are related to this phenomenon, namely the giant protein titin.
Summary of disuse
 Atrophy is the most striking consequence of disuse, especially type I fibers
 Minority of fibers undergo necrosis
 Increase in connective tissue
 Muscles develop smaller twitch and tetanic tensions, beyond those expected on
the basis of atrophy
 Tendency for fiber type switching, slowfast, with attendant changes in the
isoforms of myofibrillar proteins
 Spread of AChRs beyond the neuromuscular junction
 Diminished resting membrane potential
 Abnormal motor nerve terminals, showing both signs of degeneration and
sprouting
 Loss of motor drive, such that the motor units cannot be recruited fully
Fig. 3 Summary of the effects of disuse
Clinical relevance
 Prolonged bedrest
 Casting
 Acute quadriplegic myopathy
 BoTox