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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 1

Muscle stem cell dysregulation during development of neonatal contractures.

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Muscle stem cell dysregulation during development of neonatal contractur...
(A) Immunohistochemistry for Pax7 in biceps from contralateral and 2 weeks after neonatal brachial plexus injury (NBPI). Arrows indicate Pax7+ cells. (B) Quantification of biceps sections immunostained with Pax7 and MyoD antibodies to assess stage of muscle stem cell (MuSC) quiescence and activation. The number of Pax7+MyoD– (quiescent), Pax7+MyoD+ (activated), and Pax7–MyoD+ (differentiated) cells were normalized to total nuclei (n = 4 each for contralateral and NPBI). (C) Experimental scheme for BrdU treatment during the initial 2 weeks after NBPI. (D) Representative images (left) of immunostaining with Pax7 and BrdU antibodies in contralateral and NBPI muscle. Arrows show Pax7+BrdU+ cells and arrowheads show Pax7+BrdU– cells. Quantification (right) of proliferating MuSCs (Pax7+BrdU+) as a percentage of total Pax7+ cells (n = 7 each for contralateral and NBPI). (E) Representative images (left) showing BrdU+ myonuclei, defined as being BrdU+ and entirely within a dystrophin+ myofiber, as an indicator of myonuclear accretion. White arrows indicate a BrdU+ myonucleus, whereas yellow arrows show a BrdU– myonucleus. Quantification (right) of the percentage of myofibers containing a BrdU+ nucleus (n = 7 each for contralateral and NBPI). Data are presented as mean ± SD. Because all comparisons were done to the contralateral, unoperated forelimbs, statistical analyses were performed with paired, 2-tailed Student’s t tests except for B where Wilcoxon’s signed-rank test was used for Pax7+MyoD+ biceps due to non-normal distributions. *P < 0.05, **P < 0.01, ***P < 0.001. Scale bars: 100 μm. NS, not significant.

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