Timing of Proteasome Inhibition for Prevention of Muscle Contractures in Neonatal Brachial Plexus Injury
| Autor: | Marianne Emmert, Kritton Shay-Winkler, Sia Nikolaou, Qingnian Goh, Roger Cornwall |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | SSRN Electronic Journal. |
| ISSN: | 1556-5068 2017-0084 |
| DOI: | 10.2139/ssrn.3684390 |
| Popis: | Background: Neonatal brachial plexus injury (NBPI) causes disabling and incurable contractures, or limb stiffness, which result from proteasome-mediated protein degradation impairing the longitudinal growth of neonatally denervated muscles. We recently showed in a mouse model that the 20S proteasome inhibitor, bortezomib, prevents contractures after NBPI. Given that contractures uniquely follow neonatal denervation, the current study tests the hypothesis that proteasome inhibition during a finite window of neonatal development can prevent long-term contracture development. Methods: We used a mouse model of NBPI in which neonatal forelimb denervation at P5 causes shoulder and elbow contractures 4 weeks post-denervation. We first outlined the minimum period for proteasome inhibition to prevent contractures 4 weeks post-NBPI by treating mice with saline or bortezomib for varying durations between P8 and P32. We then compared the ability of varying durations of longer-term proteasome inhibition to prevent contractures at 8 and 12 weeks post-NBPI. Elbow and shoulder contractures, elbow flexor muscle length, and proteasome catalytic subunit activity were assessed. Findings: Proteasome inhibition can be delayed 3-4 days after denervation but is required throughout skeletal growth to prevent contractures long-term. Proteasome inhibition becomes less effective in preventing contractures beyond the neonatal period. The therapeutic effect of bortezomib is associated with attenuation of 20S proteasome β1 subunit activity. Interpretation: Temporary neonatal proteasome inhibition does not prevent contractures long-term. Instead, neonatal denervation causes a permanent longitudinal growth deficiency that must be continuously ameliorated during skeletal growth. Additional mechanisms must be explored to reduce the risk of toxicity from long-term proteasome inhibition. Funding Statement: This work was supported by grants to RC from the National Institutes of Health (NIH) (R01HD098280-01) and Pediatric Orthopaedic Society of North America (POSNA), as well as funding from the Cincinnati Children’s Hospital Division of Orthopaedic Surgery and Junior Cooperative Society. Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All mice were handled according to approved institutional animal care and use committee (IACUC) protocols (#2017-0084) of the Cincinnati Children’s Hospital Medical Center. All surgeries were performed under isoflurane anesthesia, and every effort was made to minimize suffering. |
| Databáze: | OpenAIRE |
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