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Effects of Growth Hormone Therapy on Axonal Regeneration, Muscle Atrophy, Schwann Cell Proliferation and End-Organ Reinnervation Following Nerve Injury and Repair
Sami Tuffaha, MD; J. Budihardjo; K. Sarhane; M. Khosheim; D. Song; J. Broyles; R. Salvatori; Kenneth Means; James Higgins; Jaimie T. Shores, MD; Ahmet Hoke; Damon Cooney; W.P. Andrew Lee, MD; G. Brandacher, MD
Plastic and Reconstructive Surgery, Johns Hopkins Medical Institutions, Baltimore, MD
Purpose: Poor outcomes following delayed and proximal nerve repairs result from a prolonged period of latency prior to reinnervation of distal targets. Denervated muscle undergoes atrophic changes involving permanent loss of myofibrils and motor endplates, and the degree of atrophy increases with the duration of denervation. Chronic denervation also results Schwann cell (SC) senescence. Growth hormone (GH) therapy has the potential to accelerate and augment axonal regeneration, while also acting directly on denervated muscle and SCs to minimize atrophy prior to reinnervation. The purpose of this study is to assess the effects of GH therapy on axonal regeneration, SC and muscle maintenance, and end-organ reinnervation in a nerve injury and repair model.
Methods: Male Sprague-Dawley rats underwent sciatic nerve transection-and-repair and femoral nerve transection without repair and received either daily subcutaneous GH (0.4 mg/day) or no treatment (N=8 per group). To assess GH activity, serum IGF-1 levels were measured at baseline, 2 weeks and 5 weeks, and body weights were measured weekly. All animals were sacrificed at 5 weeks and tissues were collected for analysis. Axonal regeneration was assessed by sciatic nerve histomorphometry distal to the repair site. SC proliferation within the denervated femoral nerve was determined by counting the number of cells that co-stain for Ki67 and S100. Muscle atrophy was determined by quantifying skeletal muscle fiber cross-sectional area within the gastrocnemius muscle. Percent reinnervation of motor endplates within soleus muscle was calculated.
Result: GH treated animals demonstrated greater percent increase in body weight (14.2±0.84 vs. 7.5±0.02, p<0.65), greater number of regenerating myelinated axons (13876±2036 vs. 8645±3279, p<0.05), greater percent reinnervation of motor endplates (75.8±8.7 vs. 38.2±22.6, p<0.05, figure 1), and greater muscle fiber cross-sectional area (738.5±214.4 vs. 536.8±162.6, p=0.053, figure 2) as compared to controls. Serum IGF-1 levels and quantification of proliferating SCs are still pending.
Conclusions: GH therapy may improve outcomes following nerve injury and repair by accelerating axonal regeneration, minimizing muscle atrophy and SC senescence, and promoting muscle reinnervation.
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