Abstract
At sufficient dose, intramuscular injection of Botulinum toxin A causes muscle wasting that is physiologically consistent with surgical denervation and other types of neuromuscular dysfunction. The aim of this study was to clarify early molecular and micro-RNA alterations in skeletal muscle following Botulinum toxin A-induced muscle paralysis. Quadriceps were analyzed for changes in expression of micro- and messenger RNA and protein levels after a single injection of 0.4, 2 or 4U Botulinum toxin A (/100g body weight). After injection with 2.0U Botulinum toxin A, quadriceps exhibited significant reduction in muscle weight and increased levels of ubiquitin ligase proteins at 7, 14 and 28 days. Muscle miR-1 and miR-133a/b levels were decreased at these time points, whereas a dose-responsive increase in miR-206 expression at day 14 was observed. Expression of the miR-133a/b target genes RhoA, Tgfb1 and Ctfg, and the miR-1/206 target genes Igf-1 and Hdac4, were upregulated at 28 days after Botulinum toxin A injection. Increased levels of Hdac4 protein were observed after injection, consistent with anticipated expression changes in direct and indirect Hdac4 target genes, such as Myog. Our results suggest Botulinum toxin A-induced denervation of muscle shares molecular characteristics with surgical denervation and other types of neuromuscular dysfunction, and implicates miR-133/Tgf-β1/Ctfg and miR-1/Hdac4/Myog signaling during the resultant muscle atrophy.
Highlights
In addition to cosmetic applications, intramuscular injection of Botulinum toxin A (BoNT/A) has been used to treat a range of conditions with underlying muscle dystonia, including facial palsy, pain and muscle spasticity [1,2,3,4]
At day 14, we observed a significant increase of Forkhead box O1 (Foxo1) transcription factor, one of several factors that mediate upregulation of atrophy related ubiquitin ligases (Fig 1C; [59, 60])
We did not observe significantly altered expression of nicotinic acetylcholine receptor (nAChR) Chrna1 and Chrng which previously were found to be regulated with denervation and BoNT/A-induced skeletal muscle atrophy [63]; there was an increase of the early response gene muscle specific tyrosine kinase receptor (Musk) at days 7 and 14
Summary
In addition to cosmetic applications, intramuscular injection of Botulinum toxin A (BoNT/A) has been used to treat a range of conditions with underlying muscle dystonia, including facial palsy, pain and muscle spasticity [1,2,3,4]. This neurotoxin acts by targeting SNARE protein synaptosomal-associated protein 25 (SNAP-25) for cleavage, which prevents the regulated secretion of neurotransmitter acetylcholine (Ach) at the neuromuscular junction (NMJ). Inhibition is transient, lasting about 3–4 months in humans and about 4 weeks in mice [3], and recovery involves synaptic remodeling of the NMJ. At sufficient dose, BoNT/A causes rapid muscle atrophy, a response that is conserved across species [5, 6].
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