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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. 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. 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 IV. V. VI. 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. 2. 3. 4. 5. 6. 7. 8. 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 Guillain-Barre Syndrome (GBS) Amyotrophic Lateral Sclerosis Post-polio syndrome Disuse______________________________________________________________ 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, slowfast, 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