Brachial plexus birth injury and cerebral palsy lead to a common contracture phenotype characterized by reduced functional muscle length and strength

Nikolaou, Sia; Garcia, Micah C.; Long, Jason; Allgier, Allison; Goh, Qingnian; Cornwall, Roger

doi:10.3389/fresc.2022.983159

Cited by 7 publications

(5 citation statements)

References 62 publications

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“…While length is an important facet of muscle development, the underlying mechanism(s) that drive longitudinal muscle growth remains poorly understood [56,57]. This dearth in our current understanding severely impedes clinical efforts to treat myobrevopathies – disorders stemming from muscle shortness [58]. By uncoupling muscle width and length, we discover that the neurological environment plays a vital role in differentially regulating cross‐sectional and longitudinal muscle growth.…”

Section: Discussionmentioning

confidence: 99%

The role of sympathetic innervation in neonatal muscle growth and neuromuscular contractures

et al. 2023

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Neonatal brachial plexus injury (NBPI), a leading cause of pediatric upper limb paralysis, results in disabling and incurable muscle contractures that are driven by impaired longitudinal growth of denervated muscles. A rare form of NBPI, which maintains both afferent and sympathetic muscle innervation despite motor denervation, protects against contractures. We have previously ruled out a role for NRG/ErbB signaling, the predominant pathway governing antegrade afferent neuromuscular transmission, in modulating the formation of contractures. Our current study therefore investigated the contributions of sympathetic innervation of skeletal muscle in modulating NBPI‐induced contractures. Through chemical sympathectomy and pharmacologic modification with a β2‐adrenergic agonist, we discovered that sympathetic innervation alone is neither required nor sufficient to modulate contracture formation in neonatal mice. Despite this, sympathetic innervation plays an intriguing sex‐specific role in mediating neonatal muscle growth, as the cross‐sectional area (CSA) and volume of normally innervated male muscles were diminished by ablation of sympathetic neurons and increased by β‐adrenergic stimulation. Intriguingly, the robust alterations in CSA occurred with minimal changes to normal longitudinal muscle growth as determined by sarcomere length. Instead, β‐adrenergic stimulation exacerbated sarcomere overstretch in denervated male muscles, indicating potentially discrete regulation of muscle width and length. Future investigations into the mechanistic underpinnings of these distinct aspects of muscle growth are thus essential for improving clinical outcomes in patients affected by muscle disorders in which both length and width are affected.

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Section: Discussionmentioning

confidence: 99%

The role of sympathetic innervation in neonatal muscle growth and neuromuscular contractures

et al. 2023

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“…To this end, our laboratory developed a mouse model of neonatal brachial plexus injury (NBPI), and initially showed that contractures are caused by deficient longitudinal growth in denervated muscles [8][9][10][11] . Other investigators have subsequently observed this deficit in muscle length clinically in children and infants [12][13][14] , as well as replicated this deficit using similar rodent models 15,16 . Our more recent findings revealed that this impairment is driven by elevated levels of muscle protein degradation 17 .…”

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confidence: 74%

The Relative Efficacy of Available Proteasome Inhibitors in Preventing Muscle Contractures Following Neonatal Brachial Plexus Injury

Das,

Shay-Winkler,

Emmert

et al. 2024

Journal of Bone and Joint Surgery

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Background: Contractures following neonatal brachial plexus injury (NBPI) are associated with growth deficits in denervated muscles. This impairment is mediated by an increase in muscle protein degradation, as contractures can be prevented in an NBPI mouse model with bortezomib (BTZ), a proteasome inhibitor (PI). However, BTZ treatment causes substantial toxicity (0% to 80% mortality). The current study tested the hypothesis that newer-generation PIs can prevent contractures with less severe toxicity than BTZ. Methods: Unilateral brachial plexus injuries were surgically created in postnatal (5-day-old) mice. Following NBPI, mice were treated with either saline solution or various doses of 1 of 3 different PIs: ixazomib (IXZ), carfilzomib (CFZ), or marizomib (MRZ). Four weeks post-NBPI, mice were assessed for bilateral passive range of motion at the shoulder and elbow joints, with blinding to the treatment group, through an established digital photography technique to determine contracture severity. Drug toxicity was assessed with survival curves. Results: All PIs prevented contractures at both the elbow and shoulder (p < 0.05 versus saline solution controls), with the exception of IXZ, which did not prevent shoulder contractures. However, their efficacies and toxicity profiles differed. At lower doses, CFZ was limited by toxicity (30% to 40% mortality), whereas MRZ was limited by efficacy. At higher doses, CFZ was limited by loss of efficacy, MRZ was limited by toxicity (50% to 60% mortality), and IXZ was limited by toxicity (80% to 100% mortality) and loss of efficacy. Comparisons of the data on these drugs as well as data on BTZ generated in prior studies revealed BTZ to be optimal for preventing contractures, although it, too, was limited by toxicity. Conclusions: All of the tested second-generation PIs were able to reduce NBPI-induced contractures, offering further proof of concept for a regulatory role of the proteasome in contracture formation. However, the narrow dose ranges of efficacy for all PIs highlight the necessity of precise proteasome regulation for preventing contractures. Finally, the substantial toxicity stemming from proteasome inhibition underscores the importance of identifying muscle-targeted strategies to suppress protein degradation and prevent contractures safely. Clinical Relevance: Although PIs offer unique opportunities to establish critical mechanistic insights into contracture pathophysiology, their clinical use is contraindicated in patients with NPBI at this time.

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“…While length is an important facet of muscle development, the underlying mechanism(s) that drive longitudinal muscle growth remains poorly understood [56,57]. This dearth in our current understanding severely impedes clinical efforts to treat myobrevopathiesdisorders stemming from muscle shortness [58]. By uncoupling muscle width and length, we discover that the neurological environment plays a vital role in differentially regulating cross-sectional and longitudinal muscle growth.…”

Section: Discussionmentioning

confidence: 95%

The Role of Sympathetic Innervation in Neonatal Muscle Growth and Neuromuscular Contractures

Runkel

Tarabishi

Shay-Winkler

et al. 2023

Preprint

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Neonatal brachial plexus injury (NBPI), a leading cause of pediatric upper limb paralysis, results in disabling and incurable muscle contractures that are driven by impaired longitudinal growth of denervated muscles. A rare form of NBPI, which maintains both afferent and sympathetic muscle innervation despite motor denervation, protects against contractures. We have previously ruled out a role for NRG/ErbB signaling, the predominant pathway governing antegrade afferent neuromuscular transmission, in modulating the formation of contractures. Our current study therefore investigated the contributions of sympathetic innervation of skeletal muscle in modulating NBPI-induced contractures. Through chemical sympathectomy and pharmacologic modification with a β2-adrenergic agonist, we discovered that sympathetic innervation alone is neither required nor sufficient to modulate contracture formation in neonatal mice. Despite this, sympathetic innervation plays an intriguing sex-specific role in mediating neonatal muscle growth, as the cross-sectional area (CSA) and volume of normally innervated male muscles were diminished by ablation of sympathetic neurons and increased by β-adrenergic stimulation. Intriguingly, the robust alterations in CSA occurred with minimal changes to normal longitudinal muscle growth as determined by sarcomere length. Instead, β-adrenergic stimulation exacerbated sarcomere overstretch in denervated male muscles, indicating potentially discrete regulation of muscle width and length. Future investigations into the mechanistic underpinnings of these distinct aspects of muscle growth are thus essential for improving clinical outcomes in patients affected by muscle disorders in which both length and width are affected.

show abstract

Brachial plexus birth injury and cerebral palsy lead to a common contracture phenotype characterized by reduced functional muscle length and strength

Cited by 7 publications

References 62 publications

The role of sympathetic innervation in neonatal muscle growth and neuromuscular contractures

The role of sympathetic innervation in neonatal muscle growth and neuromuscular contractures

The Relative Efficacy of Available Proteasome Inhibitors in Preventing Muscle Contractures Following Neonatal Brachial Plexus Injury

The Role of Sympathetic Innervation in Neonatal Muscle Growth and Neuromuscular Contractures

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