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Background: Contractures following neonatal brachial plexus injury (NBPI) are associated with growth deficits in denervated muscles. This impairment is mediated by an increase in muscle protein degradation, as contractures can be prevented in an NBPI mouse model with bortezomib (BTZ), a proteasome inhibitor (PI). However, BTZ treatment causes substantial toxicity (0% to 80% mortality). The current study tested the hypothesis that newer-generation PIs can prevent contractures with less severe toxicity than BTZ., Methods: Unilateral brachial plexus injuries were surgically created in postnatal (5-day-old) mice. Following NBPI, mice were treated with either saline solution or various doses of 1 of 3 different PIs: ixazomib (IXZ), carfilzomib (CFZ), or marizomib (MRZ). Four weeks post-NBPI, mice were assessed for bilateral passive range of motion at the shoulder and elbow joints, with blinding to the treatment group, through an established digital photography technique to determine contracture severity. Drug toxicity was assessed with survival curves., Results: All PIs prevented contractures at both the elbow and shoulder (p < 0.05 versus saline solution controls), with the exception of IXZ, which did not prevent shoulder contractures. However, their efficacies and toxicity profiles differed. At lower doses, CFZ was limited by toxicity (30% to 40% mortality), whereas MRZ was limited by efficacy. At higher doses, CFZ was limited by loss of efficacy, MRZ was limited by toxicity (50% to 60% mortality), and IXZ was limited by toxicity (80% to 100% mortality) and loss of efficacy. Comparisons of the data on these drugs as well as data on BTZ generated in prior studies revealed BTZ to be optimal for preventing contractures, although it, too, was limited by toxicity., Conclusions: All of the tested second-generation PIs were able to reduce NBPI-induced contractures, offering further proof of concept for a regulatory role of the proteasome in contracture formation. However, the narrow dose ranges of efficacy for all PIs highlight the necessity of precise proteasome regulation for preventing contractures. Finally, the substantial toxicity stemming from proteasome inhibition underscores the importance of identifying muscle-targeted strategies to suppress protein degradation and prevent contractures safely., Clinical Relevance: Although PIs offer unique opportunities to establish critical mechanistic insights into contracture pathophysiology, their clinical use is contraindicated in patients with NPBI at this time., Competing Interests: Disclosure: This study received funding from National Institutes of Health grant R01HD098280-01 and the Cincinnati Children’s Hospital Junior Cooperative Society. The funding sources were not involved at any stage in the research investigation and manuscript preparation. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H837 )., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)