Artikel
Pharmacologic Prevention of Contractures in Neonatal Brachial Plexus Injury
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Veröffentlicht: | 6. Februar 2020 |
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Gliederung
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Objectives/Interrogation: Contractures in neonatal brachial plexus injury (NBPI) are caused at least in part by impaired growth of denervated muscle, but the mechanism of this impaired growth is unknown. This study uses a mouse model of NBPI to assess muscle protein imbalance (synthesis vs. degradation) as a novel potential target to prevent contractures in NBPI.
Methods: Unilateral C5-T1 NBPIs were surgically created in 5-day-old mice, which reliably causes shoulder and elbow contractures 4 weeks post-NBPI. Protein synthesis was measured in denervated and contralateral control elbow flexor muscles 1-4 weeks post-NBPI by puromycin incorporation and by RNA and protein levels of major muscle proteins. Protein degradation was measured by K48-linkage specific polyubiquitin and RNA levels of protein degradation markers. Bortezomib, a 20S proteasome inhibitor, was then administrated systemically for 4 weeks post-NBPI to inhibit protein degradation. Contractures were measured 4 weeks post-NBPI, and muscles were assayed for proteasome activity and growth.
Results and Conclusions: NBPI did not reduce muscle protein synthesis, either in overall puromycin incorporation or in RNA and protein levels of specific major structural and contractile proteins. However, NBPI increased protein degradation, with a doubling of polyubiquitination and increased expression of MurF1, a driver of proteasome-mediated protein degradation. Bortezomib effectively prevented shoulder and elbow contractures following NBPI (p<0.001, Figure 1 [Fig. 1]). Bortezomib also blunted the denervation-induced increase in proteasome activity (p<0.001), and rescued muscle growth in volume (p<0.0001), cross-sectional area (p<0.001), and length (p=0.03). Thus, contractures in NBPI are caused by increased muscle protein degradation counteracting normal protein synthesis. Proteasome inhibition improves growth of denervated muscle and prevents contractures. This study therefore identifies the pathophysiology of contractures in NBPI and demonstrates the first successful pharmacologic strategy to prevent these contractures by targeting a causative molecular mechanism.