On the Regulation of Neuromuscular Contractures in Neonatal Muscle Growth

Abstract

Award: Excellence in Research Mentoring

Student Major: Biochemistry

Project Advisor: Qingnian Goh

Abstract: Neonatal brachial plexus injury (NBPI) causes complete muscle denervation in the upper limb, and leads to disabling muscle contractures. These contractures severely limit limb mobility, and are driven by impaired longitudinal growth of denervated muscles. A rare form of NBPI maintains afferent and sympathetic muscle innervation despite motor denervation. This type of injury is associated with normal muscle length and an absence of contractures in the affected limb. To decipher underlying mechanism(s) by which neural input governs muscle growth and contracture formation following neonatal muscle denervation, we must investigate the roles of afferent and sympathetic innervation in protecting against contractures. We have previously ruled out a role for NRG/ErbB signaling, the predominant pathway governing antegrade afferent neuromuscular transmission, in contracture modulation. In this current study, through chemical sympathectomy and pharmacologic modification with a β2-adrenergic agonist, we discover that sympathetic innervation alone is neither required nor sufficient to modulate contracture formation in neonatal mice. Despite this, sympathetic innervation plays a sex-specific role in mediating neonatal muscle growth, as cross-sectional area (CSA) of normally innervated male muscles were diminished by ablation of sympathetic neurons and increased by β-adrenergic stimulation. Intriguingly, 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 discrete regulation of muscle width and length. Future studies should elucidate the synergistic role of afferent and sympathetic innervation in contracture modulation, and further dissect the distinct pathways regulating cross-sectional and longitudinal muscle growth.