Timing of proteasome inhibition as a pharmacologic strategy for prevention of muscle contractures in neonatal brachial plexus injury
| Autor: | Kritton Shay-Winkler, Qingnian Goh, Marianne Emmert, Sia Nikolaou, Roger Cornwall |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Sarcomeres Proteasome Endopeptidase Complex Contracture sarcomerogenesis Pharmacology Protein degradation Biochemistry Article Sarcomerogenesis Bortezomib 03 medical and health sciences Mice 0302 clinical medicine neonatal brachial plexus injury Genetics medicine Animals Molecular Biology Muscle contracture Denervation proteasome inhibition denervation business.industry Neonatal Brachial Plexus Palsy muscle length medicine.disease muscle contracture 030104 developmental biology medicine.anatomical_structure Brachial plexus injury protein degradation Forelimb medicine.symptom business Proteasome Inhibitors 030217 neurology & neurosurgery Biotechnology medicine.drug |
| Zdroj: | FASEB journal : official publication of the Federation of American Societies for Experimental Biology |
| ISSN: | 1530-6860 |
| Popis: | 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. Following neonatal forelimb denervation in P5 mice, 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. Our findings revealed that proteasome inhibition can be delayed 3-4 days 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-induced attenuation of 20S proteasome β1 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-term treatment. |
| Databáze: | OpenAIRE |
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