NRG/ErbB signaling regulates neonatal muscle growth but not neuromuscular contractures in neonatal brachial plexus injury.
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ABSTRACT:
SUBMITTER: Ho BL
PROVIDER: S-EPMC7940581 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
Publications
NRG/ErbB signaling regulates neonatal muscle growth but not neuromuscular contractures in neonatal brachial plexus injury.
Ho Brendan L BL Goh Qingnian Q Nikolaou Sia S Hu Liangjun L Shay-Winkler Kritton K Cornwall Roger R
FEBS letters 20210128 5
Neonatal brachial plexus injury (NBPI) causes disabling and incurable muscle contractures that are driven by impaired growth of denervated muscles. A rare form of NBPI, which maintains afferent muscle innervation despite motor denervation, does not cause contractures. As afferent innervation regulates various aspects of skeletal muscle homeostasis through NRG/ErbB signaling, our current study investigated the role of this pathway in modulating contracture development. Through pharmacologic modif ...[more]
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Project description: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.
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Project description:BackgroundThe one-bone forearm procedure has been considered as a potential treatment for severe forearm deformities. However, its primary limitation lies in the elevated risks of nonunion and infection. In order to enhance union rates, a technical modification was introduced, aiming not only to establish end-to-end radio-ulnar fixation but also to incorporate an additional overlay and fixation between the proximal and distal radius osteotomy stumps. This technique, initially applied in a heterogeneous patient population including individuals with neurological, tumoral, and congenital conditions, yielded promising results, achieving a consolidation rate of 100% and enabling supination corrections of up to 120°.MethodsIn this study, we present a retrospective cohort of 28 patients, with an average age of 9 years, all afflicted by forearm supination contracture exceeding 90° secondary to neonatal brachial plexus injury. These patients underwent treatment with the modified technique.ResultsThe mean correction achieved in forearm rotation was 116°, and the average follow-up period extended to 43 months. Remarkably, all patients exhibited bone union within an average period of 6.6 weeks, without any complications.ConclusionOur findings underscore the efficacy of this modified technique, which enables substantial rotational corrections, boasts a high union rate, and maintains a low incidence of complications. This approach is particularly valuable for young patients suffering from neonatal brachial plexus injury with severe fixed supination deformities.Case series level of evidenceIV.
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Project description:Neonatal brachial plexus injury (NBPI) causes disabling and incurable muscle contractures that result from impaired longitudinal growth of denervated muscles. This deficit in muscle growth is driven by increased proteasome-mediated protein degradation, suggesting a dysregulation of muscle proteostasis. The myostatin (MSTN) pathway, a prominent muscle-specific regulator of proteostasis, is a putative signaling mechanism by which neonatal denervation could impair longitudinal muscle growth, and thus a potential target to prevent NBPI-induced contractures. Through a mouse model of NBPI, our present study revealed that pharmacologic inhibition of MSTN signaling induces hypertrophy, restores longitudinal growth, and prevents contractures in denervated muscles of female but not male mice, despite inducing hypertrophy of normally innervated muscles in both sexes. Additionally, the MSTN-dependent impairment of longitudinal muscle growth after NBPI in female mice is associated with perturbation of 20S proteasome activity, but not through alterations in canonical MSTN signaling pathways. These findings reveal a sex dimorphism in the regulation of neonatal longitudinal muscle growth and contractures, thereby providing insights into contracture pathophysiology, identifying a potential muscle-specific therapeutic target for contracture prevention, and underscoring the importance of sex as a biological variable in the pathophysiology of neuromuscular disorders.
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Project description:Facilitating children's understanding of their medical condition can improve health outcomes and psychosocial well-being. To inform how medical information is delivered, an interpretive qualitative approach was used to explore children's understanding of their brachial plexus birth injury. In-depth interviews of children with brachial plexus birth injuries (n = 8) and their caregivers (n = 10) were conducted individually and as a child-caregiver dyad. Thematic analysis of interview data found that children primarily understood their injury through lived experiences of functional and psychosocial concerns related to movement and appearance of the affected limb, rather than medical information. Children's ability to learn about diagnostic and prognostic information was influenced by age, emotional readiness, and background knowledge. In receiving information about their medical condition, children needed greater support in understanding their prognosis and its implications on their future. These narratives indicate the importance of addressing the primary functional and psychosocial concerns to contextualize medical information and ascertain the emotional readiness of children with brachial plexus birth injuries in information delivery approaches.
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