Studies on neurotrophic regulation of murine skeletal muscle

Abstract

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. After surgical denervation, TTX resistant action potentials were present in all fibers on the 3rd day and their rate of rise and amount of overshoot reached peak values at the 5th day. BoTx poisoning failed, despite causing complete paralysis, to induce TTX resistant action potentials in all fibers and their average rate of rise was at all times (4-12 days) only about 1/2 that in denervated fibers. Similarly BoTx poisoning induced a smaller increase than surgical denervation in the number of extrajunctional ACh receptors, measured as 3H-labeled Naja naja siamensis .alpha.-neurotoxin binding sites. Surgical denervation of BoTx poisoned muscles induced TTX resistant action potentials in all fibers and their rate of rise and amount of overshoot were 2-3 times those in BoTx poisoned muscles only. Denervation significantly increased the binding of labeled .alpha.-neurotoxin. These effects of denervation were prevented by the administration of actinomycin D, a blocker of protein synthesis. Administration of the .alpha.-neurotoxin to BoTx poisoned animals resulted in the appearance of TTX resistant action potentials in all fibers and in a significant increase in their rate of rise and overshoot. Despite causing complete paralysis, BoTx is less effective than surgical denervation in inducing denervatory changes in skeletal muscle. BoTx poisoned nerve probably 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.