How muscles recover from paresis and atrophy after intramuscular injection of botulinum toxin A: Study in juvenile rats

Abstract

Botulinum toxin A (BoNT-A) is a potent biological toxin widely used for the management of skeletal muscle spasticity or dynamic joint contracture. Intramuscular injection of BoNT-A causes muscle denervation, paresis, and atrophy. This clinical effect of botulinum toxin A lasts 3 to 6 months, and injected muscle eventually regains muscle mass and recovers muscle function. The goal of the present study was to characterize the molecular and cellular mechanisms leading to neuromuscular junction (NMJ) regeneration and skeletal muscle functional recovery after BoNT-A injection. Fifty-six 1-month-old Sprague-Dawley rats were used. Botulinum toxin A was injected into the left gastrocnemius muscle at a dosage of 6 units/kg body weight. An equivalent volume of saline was injected into the right gastrocnemius muscle to serve as control. The gastrocnemius muscle samples were harvested from both hind limbs at 3 days, 7 days, 15 days, 30 days, 60 days, 90 days, 180 days, and 360 days after administration of toxin. In addition, the gastrocnemius muscles from 1-month-old rats with no injections were harvested to serve as uninjected control group. Muscle samples were processed and mRNA was extracted. Real-time polymerase chain reaction (PCR) and gene microarray technology were used to identify key molecules involved in NMJ stabilization and muscle functional recovery. More than 28,000 rat genes were analyzed and approximately 9000 genes are expressed in the rat gastrocnemius muscle. Seven days following BoNT-A injection, 105 genes were upregulated and 59 genes were downregulated. Key molecules involved in neuromuscular junction (NMJ) stabilization and muscle functional recovery were identified and their time course of gene expression following BoNT-A injection were characterized. This animal study demonstrates that following intramuscular injection of BoNT-A, there is a sequence of cellular events that eventually leads to NMJ stabilization, remodeling, and myogenesis and muscle functional recovery. This recovery process is divided into two stages (aneural and neural) and that the IGF-1 signaling pathway play a central role in the process. ß

Spasticity Patterns of Hand Muscles and Botulinum Toxin Therapy Application in Patients With Cerebral Palsy With Upper Limb Involvement

“…The need in single-step multilevel BTA administration to patients of low weight often leads to the drug's dosage reduction for each functional level or selection of priority muscles for botulinum therapy on that stage of the patient's motor development. Evaluation of tonus dynamics in hand muscles in patients with CP after the primary singular BTA injections showed the presence of common trend in all the observed children -significant spasticity reduction and motion volume increase in joints 1 and 3 months after the injection and gradual muscular tonus increase by the 6 th month of observation; this corresponds with the results of other botulinum therapy efficacy observations both for lower and upper extremities' muscles [4,28,30,31]. In several patients, spasticity exceeded the initial level by the end of the observation period or within 6 post-injection months.…”

Insulin growth factors may explain relationship between spasticity and skeletal muscle size in men with spinal cord injury

“…IGF-1 was upregulated 3-7 d after botulinum toxin A injection to the gastrocnemius muscle of the rats. The upregulation of IGF-1 enhances the release of myogenic factors that, in turn, could activate the acetylcholine receptors and trigger spasticity [27].…”

Drug Insight: biological effects of botulinum toxin A in the lower urinary tract

“…All serotypes block transmission at neuromuscular junctions to varying degrees, but the effects of botulinum neurotoxin type A (BTX-A) are the most prolonged; this serotype has been the most extensively studied, mainly in striated muscle. [1][2][3] BTX-A has received regulatory approval for use in several disorders characterized by excessive muscle contractility or tonus in striated muscle (e.g. cervical dystonia, blepharospasm, hemifacial spasm, and limb spasticity) or overactive secretion of sweat (e.g.…”