Growth Hormone Enhanced Recovery After Chronic Denervation Injury: Augmenting Axonal Regeneration, Promoting Motor Reinnervation, and Improving Muscle Function
Joseph Lopez, MD MBA, Amy Quan, MPH, Joshua Budihardjo, BS, Kim X. Sinan, BS, Kiron Koshy, MBBS, Howard D. Wang, MD, Chris Cashman, PhD, Ahmet Hoke, MD PhD, Sami Tuffaha, MD, WP Andrew Lee, MD, Gerald Brandacher, MD.
Johns Hopkins Hospital, Baltimore, MD, USA.
Introduction Several experimental studies suggest that growth hormone-based therapies have the potential to accelerate and augment axonal regeneration while simultaneously act directly on muscle and Schwann cells (SCs) to minimize denervation atrophy prior to re-innervation. The purpose of this study was to assess the impact of growth hormone (GH) therapy on preventing the deleterious effects of chronic denervation (CD) injury on nerve regeneration and resulting muscle function. We hypothesized that systemic GH therapy can maintain chronically-denervated muscle and SCs, accelerate axonal regeneration, and improve murine extremity function in the setting of chronic denervation (CD) by preserving muscle mass and promoting motor reinnervation.
Methods We utilized a newly-developed, rat forelimb CD model to assess the effects of GH therapy on: a) improving nerve regeneration; and b) preventing muscle atrophy and augmenting muscle re-innervation and function. Four groups of rats were examined: (1) Group-1 (n = 8) underwent 8 weeks of median nerve CD injury followed by repair; (2) Group-2 (experimental, n = 8) underwent 8 weeks of median nerve CD followed by repair and treatment with highly purified lyophilized pituitary porcine GH (0.6 mg/day); (3) Group-3 animals (n = 8) underwent no median nerve CD injury; (4) Group-4 animals (n = 8) were naïve controls. All animals underwent weekly muscle functional testing followed by median nerve and flexor muscle harvest for nerve histomorphometry, muscle weight, atrophy, and re-innervation analysis. To enable the assessment of the effects of GH therapy on maintaining denervated muscle and SCs: Group-1 animals also underwent 8 weeks of contralateral sciatic nerve CD; Group-2 animals underwent 8 weeks of sciatic nerve CD (w/ GH treatment as stated above); Group-3 animals underwent 1 week of sciatic nerve CD; and Group-4 animals underwent no sciatic nerve CD. The sciatic nerve and lateral gastrocnemius muscle were harvested after completion of sciatic nerve CD injury time point to assess for SC proliferation/senescence markers (via qPCR) and muscle atrophy (via muscle weight and cross-sectional area muscle staining).
Results Median nerve regeneration was higher in GH-treated animals when compared to untreated controls as measured by axon density (p < 0.005), axon diameter (p < 0.0001), and myelin thickness (p < 0.0001). Furthermore, GH improved muscle re-innervation (27.9% vs 38.0% NMJs re-innervated; p < 0.02) and prevented muscle atrophy (865±48.3 vs 1081±101.4 µM2; p < 0.02). GH-treated rats demonstrated greater functional muscle recovery as compared to untreated controls (hand grip: 1.8 ± 0.3 N vs. 1.0 ± 0.1 N, p=0.001). Lastly, Group 2 animals demonstrated higher expression of SC proliferation and migration markers, c-Jun & erbB-3, and less muscle atrophy (0.21 ± 0.02 g vs. 0.17 ± 0.01 g; P=0.55) when compared to Group 1 at 8 weeks after sciatic nerve CD.
Conclusion Systemic GH therapy can improve nerve regeneration and maintain chronically-denervated muscle by promoting re-innervation and subsequent muscle function.
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