Denervation and Disuse, February 8, 2006 Denervation

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Denervation and Disuse, February 8, 2006

Changes in Motor Axons and Neuromuscular Junctions

  1. 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

  1. 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

  1. 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

  1. 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.

  1. 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

  • 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

  1. 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

  1. 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

  1. 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. Fall in resting membrane potential

  2. Permeability of the fiber is altered

  3. Muscle action potential has a lower rate of rise and a longer duration.

  4. Sensitivity of the muscle fiber to ACh begins to spread out to involve the remainder of the fiber.

  5. Fibrillation potentials develop

  6. Cholinesterase concentration in the endplate falls

  7. Fast-twitch muscles become sensitive to caffeine

  8. Denervated muscle fiber stimulates sprouting

Fig. 2 Summary of the Effects of denervation

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