Long-term Effects of Botulinum Toxin on Neuromuscular Function

Abstract

Botulinum toxin causes dose-dependent long-term neuromuscular changes. The loss of tension generating capacity is almost exclusively related to muscle atrophy, because the specific tension did not change. The decreased ED10, unaltered ED50, and increased ED90 to atracurium suggest its interactions with different isoforms of receptors having varying sensitivity to atracurium. The absence of fade, despite the persistent botulinum toxin-induced denervation (increased nAChRs), suggests that the up-regulated nAChRs may have compensated for the prejunctional effects of botulinum toxin.

A Single Injection of Botulinum Toxin Decreases the Margin of Safety of Neurotransmission at Local and Distant Sites

“…This finding contrasts with observations in our previous study examining the long-term (128 days) effects of different doses (0.625U, 2.5U and 10U) of botulinum toxin on neuromuscular transmission. In that study, no differences were seen in specific muscle tensions suggesting that the prejunctional effects disappear by 128 days and muscle atrophy was the predominant reason for impaired muscle function at that time (13). Although we did not measure junctional nAChRs, total nAChRs on muscle membrane were in fact increased on day 16 and usually included up-regulation of fetal nAChRs.…”

“…Therefore, our previous study (13) evaluated the effects of botulinum toxin beyond the three months. We demonstrated that a single injection of increasing doses (0.625U, 2.5U and 10U) of botulinum toxin injected into the tibialis muscle caused dose-dependent long-term (128 days after injection) functional, pharmacological and biochemical changes at the neuromuscular junction (13). However, the onset and early effects of botulinum toxin remain unclear.…”

Role of MyoD in denervated, disused, and exercised muscle

“…39,72 However, different denervation models affect the MyoD response and changes in muscle fiber type composition in inconsistent ways. The denervation-induced upregulation of MyoD might be interpreted as an attempt of the muscle to regain sensitivity to neural activity, since the expression of the acetylcholine receptor was found to increase after denervation 14,34,37,73,74 and MyoD has been shown to regulate the expression of the acetylcholine receptor alpha subunit. 88 The upregulation of MyoD can be partially reversed by electrical stimulation of the denervated muscle, further demonstrating the effect of neural activity on MyoD expression.…”

“…34 Even 128 days after chemodenervation by Btx the concentration of the acetylcholine receptor protein in the rat tibialis anterior muscle was found to be significantly elevated compared to the noninjected contralateral leg and saline-injected controls. 37 In contrast, another study investigating the expression of the alpha, beta, gamma, delta, and epsilon subunits of the acetylcholine receptor in surgically denervated rat gastrocnemius muscle showed that, after an increase in expression within the first week, most subunits decreased after 90, 180, and 360 days of denervation. Yet MyoD expression was also only increased 7 and 14 days after surgery, which may account for the diminished acetylcholine response.…”

“…47 This latter evidence suggests that ciliary neurotrophic factor exerts myotrophic effects by attenuating the morphological and functional changes associated with denervation contrary to the previously described hypothesis. An increase in MyoD expression might also be interpreted as an attempt of the muscle to regain sensitivity to neural activity, since expression of the acetylcholine receptor increases after denervation 14,34,37,73,74 and MyoD has been shown to regulate the expression of the acetylcholine receptor alpha subunit. 88 Furthermore, electrical activity is thought to phosphorylate proteins of the myogenic regulatory factor family, resulting in reduced activation of acetylcholine receptor expression in electrically active muscle.…”