Systems analysis of transcriptional data provides insights into muscle's biological response to botulinum toxin

Authors

  • Kavitha Mukund MS,

    1. Bioinformatics and System Biology Graduate Program, University of California San Diego, La Jolla, California, USA
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  • Margie Mathewson MS,

    1. Department of Bioengineering, University of California San Diego, La Jolla, California, USA
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  • Viviane Minamoto PT, PhD,

    1. Department of Orthopaedic Surgery, University of California San Diego, La Jolla, California, USA
    2. Department of Radiology, University of California San Diego, La Jolla, California, USA
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  • Samuel R. Ward PT, PhD,

    1. Department of Orthopaedic Surgery, University of California San Diego, La Jolla, California, USA
    2. Department of Radiology, University of California San Diego, La Jolla, California, USA
    3. Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
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  • Shankar Subramaniam PhD,

    Corresponding author
    1. Bioinformatics and System Biology Graduate Program, University of California San Diego, La Jolla, California, USA
    2. Department of Bioengineering, University of California San Diego, La Jolla, California, USA
    3. Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, USA
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  • Richard L. Lieber PhD

    Corresponding author
    1. Department of Bioengineering, University of California San Diego, La Jolla, California, USA
    2. Department of Orthopaedic Surgery, University of California San Diego, La Jolla, California, USA
    3. Veterans Affairs San Diego Healthcare System, La Jolla, California, USA
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  • This study was financially supported by grants from the Department of Veterans Affairs (RX000670 to R.L.); the National Institutes of Health (R24HD050837 to R.L. and AR057013 to S.W.), Allergan, Inc. (to R.L.); the National Heart, Lung, and Blood Institute (HL087375-02, HL106579, and HL108735 to S.S.); and the National Science Foundation (STC-0939370 to S.S.).

ABSTRACT

Introduction: This study provides global transcriptomic profiling and analysis of botulinum toxin A (BoNT-A)–treated muscle over a 1-year period. Methods: Microarray analysis was performed on rat tibialis anterior muscles from 4 groups (n = 4/group) at 1, 4, 12, and 52 weeks after BoNT-A injection compared with saline-injected rats at 12 weeks. Results: Dramatic transcriptional adaptation occurred at 1 week with a paradoxical increase in expression of slow and immature isoforms, activation of genes in competing pathways of repair and atrophy, impaired mitochondrial biogenesis, and increased metal ion imbalance. Adaptations of the basal lamina and fibrillar extracellular matrix (ECM) occurred by 4 weeks. The muscle transcriptome returned to its unperturbed state 12 weeks after injection. Conclusions: Acute transcriptional adaptations resemble denervated muscle with some subtle differences, but resolved more quickly compared with denervation. Overall, gene expression across time correlates with the generally accepted BoNT-A time course and suggests that the direct action of BoNT-A in skeletal muscle is relatively rapid. Muscle Nerve 50: 744–758, 2014

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