Format

Send to

Choose Destination
JCI Insight. 2019 Dec 5;4(23). pii: 128454. doi: 10.1172/jci.insight.128454.

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

Author information

1
Division of Orthopaedic Surgery, and.
2
Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
3
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
4
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
5
Department of Orthopaedic Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

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.

KEYWORDS:

Muscle Biology; Neuromuscular disease

PMID:
31661460
DOI:
10.1172/jci.insight.128454
Free full text

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation
Loading ...
Support Center