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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\u2010term contracture development. Following neonatal forelimb denervation in P5 mice, we first outlined the minimum period for proteasome inhibition to prevent contractures 4\u00a0weeks post\u2010NBPI by treating mice with saline or bortezomib for varying durations between P8 and P32. We then compared the ability of varying durations of longer\u2010term proteasome inhibition to prevent contractures at 8 and 12\u00a0weeks post\u2010NBPI. Our findings revealed that proteasome inhibition can be delayed 3\u20104\u00a0days after denervation but is required throughout skeletal growth to prevent contractures long term. Furthermore, proteasome inhibition becomes less effective in preventing contractures beyond the neonatal period. These therapeutic effects are primarily associated with bortezomib\u2010induced attenuation of 20S proteasome \u03b21 subunit activity. Our collective results, therefore, demonstrate that temporary neonatal proteasome inhibition is not a viable strategy for preventing 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 minimize the necessary period of proteasome inhibition and reduce the risk of toxicity from long\u2010term treatment.<\/jats:p>","DOI":"10.1096\/fj.202002194","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T03:57:21Z","timestamp":1606276641000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Timing of proteasome inhibition as a pharmacologic strategy for prevention of muscle contractures in neonatal brachial plexus injury"],"prefix":"10.1096","volume":"35","author":[{"given":"Qingnian","family":"Goh","sequence":"first","affiliation":[{"name":"Division of Orthopaedic Surgery Cincinnati Children's Hospital Medical Center Cincinnati OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sia","family":"Nikolaou","sequence":"additional","affiliation":[{"name":"Division of Orthopaedic Surgery Cincinnati Children's Hospital 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