Changes produced by a hypomyelinating neuropathy in muscle and its innervation. Morphological and physiological...

The peripheral nerves of the Trembler mouse are hypomyelinated. The effects of the neuropathy on muscle and motor end-plate morphology, and on neuromuscular transmission in slow-twitch (soleus) and fast-twitch (extensor digitorum longus) muscle are reported. After forming normally, motor end-plates developed ultraterminal sprouts by about 18 days of age in deep, slow-twitch muscles. The only ultrastructural abnormality in muscle at this age was disruption of Z-lines. Ultraterminal sprouting progressed, and by about 3 months the innervation zone consisted of a mass of branching axons associated in places with cholinesterase activity. The ultrastructure of end-plates became abnormal. Fascicular atrophy was present in older Tremblers and the ultrastructural morphology of muscle fibres became disorganized with accumulation of subsarcolemmal granular material. Abnormal muscle fibres were innervated by axonal sprouts. The superficial, predominantly fast-twitch, muscles showed milder changes at all ages even though the nerves supplying them were hypomyelinated. Studies of neuromuscular transmission showed that soleus retained its slow-twitch and extensor digitorum longus its fast-twitch characteristics, and miniature end-plate potentials were of normal frequency and amplitude. The latency of end-plate potentials and the refractory period of transmission were prolonged in both soleus and extensor digitorum longus. With repetitive stimulation at 50 Hz a cyclical pattern of responses and failures occurred which was probably caused by intermittent conduction block along the peripheral nerve. Although the pathological changes in Trembler muscle were like those of partial denervation, atrophic muscles contained an abundance of axons and there was no evidence of axonal degeneration. The changes in muscle are therefore a consequence of hypomyelination without axonal loss. Since slow-twitch muscles are normally subjected to prolonged stimulation, failure of Trembler axons to conduct sustained trains of stimuli in vivo may contribute to the development of pathological changes in slow-twitch muscle. Hypomyelimated axons may be capable of conducting short bursts of impulses, however, which is the pattern of stimulation in fast-twitch muscle in vivo, so that fast-twitch muscle fibres and end-plates remain relatively spared.