Botulinum toxin A-induced muscle paralysis stimulates Hdac4 and differential miRNA expression

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 followin...

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Bibliographic Details
Published in:PloS one 2018-11, Vol.13 (11), p.e0207354
Main Authors: Worton, Leah E, Gardiner, Edith M, Kwon, Ronald Y, Downey, Leah M, Ausk, Brandon J, Bain, Steven D, Gross, Ted S
Format: Article
Language:English
Subjects:
Atrophy
Biology and Life Sciences
Body weight
Botulinum toxin
Botulinum toxin type A
Denervation
Drug dosages
Gene expression
Genes
HDAC4 protein
Injection
Insulin-like growth factor I
Kinases
Medical research
Medicine
Medicine and Health Sciences
MicroRNAs
miRNA
Muscles
Musculoskeletal system
Paralysis
Proteins
Quadriceps muscle
RhoA protein
Ribonucleic acid
RNA
Signal transduction
Skeletal muscle
Sports medicine
Surgery
Transcription factors
Transforming growth factor-b1
Ubiquitin
Ubiquitin-protein ligase
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0207354