Studies on neurotrophic regulation of murine skeletal muscle

1. A quantitative comparison was made of the effects of the paralysis caused by botulinum toxin (BoTx) type A with those of surgical denervation on the development of tetrodotoxin (TTX) resistant action potentials and of extrajunctional acetylcholine (ACh) receptors in rat and mouse skeletal muscle.2. After surgical denervation, TTX resistant action potentials were present in all fibres on the third day and their rate of rise and amount of overshoot reached peak values at the fifth day. BoTx poisoning failed, despite causing complete paralysis, to induce TTX resistant action potentials in all fibres and their average rate of rise was at all times (4-12 days) only about half that in denervated fibres. Similarly BoTx poisoning induced a smaller increase than surgical denervation in the number of extrajunctional ACh receptors, measured as (3)H-labelled Naja naja siamensis alpha-neurotoxin binding sites.3. Surgical denervation of BoTx poisoned muscles induced TTX resistant action potentials in all fibres and their rate of rise and amount of overshoot were 2-3 times those in BoTx poisoned muscles only. Denervation also significantly increased the binding of labelled alpha-neurotoxin. These effects of denervation were prevented by the administration of actinomycin D, a blocker of protein synthesis.4. Administration of the alpha-neurotoxin to BoTx poisoned animals resulted in the appearance of TTX resistant action potentials in all fibres and in a significant increase in their rate of rise and overshoot.5. The results show that, despite causing complete paralysis, BoTx is less effective than surgical denervation in inducing denervatory changes in skeletal muscle. This suggests that the BoTx poisoned nerve has an influence which suppresses the appearance of denervation signs. Since the alpha-neurotoxin blocked this influence remaining release of ACh, quantal or non-quantal, may be responsible for this neurotrophic action.