Injection of high dose botulinum-toxin A leads to impaired skeletal muscle function and damage of the fibrilar and non-fibrilar structures

Abstract

Botulinum-toxin A (BoNT/A) is used for a wide range of conditions. Intramuscular administration of BoNT/A inhibits the release of acetylcholine at the neuromuscular junction from presynaptic motor neurons causing muscle-paralysis. The aim of the present study was to investigate the effect of high dose intramuscular BoNT/A injections (6 UI = 60 pg) on muscle tissue. The gait pattern of the rats was significantly affected 3 weeks after BoNT/A injection. The ankle joint rotated externally, the rats became flat footed, and the stride length decreased after BoNT/A injection. Additionally, there was clear evidence of microstructural changes on the tissue level by as evidenced by 3D imaging of the muscles by Synchrotron Radiation X-ray Tomographic Microscopy (SRXTM). Both the fibrillar and the non-fibrillar tissues were affected. The volume fraction of fibrillary tissue was reduced significantly and the non-fibrillar tissue increased. This was accompanied by a loss of the linear structure of the muscle tissue. Furthermore, gene expression analysis showed a significant upregulation of COL1A1, MMP-2, TGF-b1, IL-6, MHCIIA and MHCIIx in the BoNT/A injected leg, while MHVIIB was significantly downregulated. In conclusion: The present study reveals that high dose intramuscular BoNT/A injections cause microstructural damage of the muscle tissue, which contributes to impaired gait.

Comparison study of the response with botulinum toxin muscle injection in the ICR mice from three different sources

“…Studies using BoNT/A have largely involved safety assessments via potency tests in laboratory animals. In addition, studies addressing mechanism and phenotype of muscle change have been reported, including those evaluating dose-dependent responses to BoNT/A muscle injection [23]. Research using laboratory animals with rodent has long been conducted on basic research and treatment of human diseases and on the pathogenesis.…”

“…ICR mice, an outbred rodent model, have been previously used for the study of BoNT/A [24]. In previous rodent experiments, muscle change through the administration of BoNT/A muscle was found at various concentrations [23], but no comparative study has been conducted with ICR mice originating from different sources. The present study investigated the response to BoNT/A injection into muscle using mice from three different sources, Korl:ICR, A:ICR, and B:ICR.…”

Muscle and tendon lengthening behaviour of the medial gastrocnemius during ankle joint rotation in children with cerebral palsy

“…botulinum toxin A injections, received by the participants might have influenced the results of this study. Some studies show microstructural changes at the tissue level in animals (Pingel et al, 2017) or have found an increase in muscle stiffness in in silico experiments (Wang, Gäverth, & Herman, 2018), whereas others report no changes in muscle stiffness (Alhusaini, Crosbie, Shepherd, Dean, & Scheinberg, 2011) after botulinum toxin A injections. Unfortunately, it is practically impossible to recruit a representative group of children with CP who have not had any interventions during their life.…”

A comparison study of prabotulinumtoxinA vs onabotulinumtoxinA in myostatin‐deficient mice with muscle hypertrophy

“…This process inhibits nerve signalling, leading to transient paralysis . Injecting BoNT‐A into muscle tissue prevents the extracellular release of acetylcholine due to protein degradation of SNAP25 and effectively leads to muscle paralysis …”