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

Abstract

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.

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

“…Notably, MRZ failed to prevent the overstretching of sarcomeres in neonatally denervated muscles, indicating a lack of improvement in functional muscle length. This result aligns with our previous reports of increased sarcomere overstretching despite an absence of contracture modification with pharmacologic stimulation of NRG/ErbB signaling and b-adrenergic signaling 36,44 , which are major pathways governing muscle spindle development [45][46][47][48] and neuromuscular junction maintenance 49 , respectively. These collective findings may indicate that PIs rescue contractures by a mechanism independent of muscle growth restoration, or that additional mechanisms other than impaired longitudinal muscle growth drive the formation of denervation-induced contractures.…”