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Proteasome inhibition preserves longitudinal growth of denervated muscle and prevents neonatal neuromuscular contractures
Sia Nikolaou, … , Douglas P. Millay, Roger Cornwall
Sia Nikolaou, … , Douglas P. Millay, Roger Cornwall
Published October 29, 2019
Citation Information: JCI Insight. 2019;4(23):e128454. https://doi.org/10.1172/jci.insight.128454.
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Research Article Muscle biology

Proteasome inhibition preserves longitudinal growth of denervated muscle and prevents neonatal neuromuscular contractures

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Abstract

Muscle contractures are a prominent and disabling feature of many neuromuscular disorders, including the 2 most common forms of childhood neurologic dysfunction: neonatal brachial plexus injury (NBPI) and cerebral palsy. There are currently no treatment strategies to directly alter the contracture pathology, as the pathogenesis of these contractures is unknown. We previously showed in a mouse model of NBPI that contractures result from impaired longitudinal muscle growth. Current presumed explanations for growth impairment in contractures focus on the dysregulation of muscle stem cells, which differentiate and fuse to existing myofibers during growth, as this process has classically been thought to control muscle growth during the neonatal period. Here, we demonstrate in a mouse model of NBPI that denervation does not prevent myonuclear accretion and that reduction in myonuclear number has no effect on functional muscle length or contracture development, providing definitive evidence that altered myonuclear accretion is not a driver of neuromuscular contractures. In contrast, we observed elevated levels of protein degradation in NBPI muscle, and we demonstrate that contractures can be pharmacologically prevented with the proteasome inhibitor bortezomib. These studies provide what we believe is the first strategy to prevent neuromuscular contractures by correcting the underlying deficit in longitudinal muscle growth.

Authors

Sia Nikolaou, Alyssa A.W. Cramer, Liangjun Hu, Qingnian Goh, Douglas P. Millay, Roger Cornwall

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Figure 4

Pharmacologic inhibition of the proteasome preserves longitudinal muscle growth and prevents contractures.

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Pharmacologic inhibition of the proteasome preserves longitudinal muscle...
(A) Experimental scheme for NBPI and bortezomib treatment. (B) Images of forelimbs showing contractures in elbow (top) and shoulder (bottom) after NBPI, which are corrected with bortezomib. (C) Quantification of contracture severity, calculated as the difference in extension (elbow) or rotation (shoulder) between NBPI and contralateral. Saline and [Gly14]-Humanin G ([Gly14]-HN) were used as controls (saline n = 9, [Gly14]-HN n = 10, 0.4 mg/kg bortezomib n = 11). (D) Schematic showing the optimized bortezomib treatment strategy. (E) Forelimb images showing the lack of contractures after NBPI in mice treated with 0.3 mg/kg bortezomib beginning on P8. (F) Contracture severity in the elbow and shoulder from the mice shown in E. The dotted line represents the severity in saline controls (from C) (elbow n = 15, shoulder n = 16). (G) Sarcomere length in the brachialis shows that 0.3 mg/kg bortezomib preserves muscle length (saline n = 9, [Gly14]-HN n = 10, 0.3 mg/kg bortezomib n = 15). (H) Whole muscle cross-sectional area (CSA) of brachialis muscles shows that bortezomib does not rescue muscle CSA (saline n = 9, [Gly14]-HN n = 10, 0.3 mg/kg bortezomib n = 15). (I) Whole muscle volume of brachialis muscles shows that bortezomib does not rescue muscle volume (saline n = 9, [Gly14]-HN n = 10, 0.3 mg/kg bortezomib n = 16). (J) Proteasome activity in denervated biceps muscles harvested 2 weeks after treatment with saline (n = 6) and 0.3 mg/kg bortezomib (n = 6), showing that bortezomib blunts the denervation-induced increase in proteasome activity. RFU, relative fluorescence units. Data are presented as mean ± SD. Statistical analysis performed with an unpaired, 2-tailed Student’s t test in C and F; and with unpaired, 2-tailed Student’s t test between groups and paired, 2-tailed Student’s t test between limbs of mice in each group in G–J. Bonferroni corrections for multiple comparisons were performed in C and G–J, and adjusted P values are reported for those data. **P < 0.01, ***P < 0.001, ****P < 0.0001.

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