Elucidating the Relative Impact of Muscle vs. Schwann Cell Denervation on Functional Recovery in a Novel Rodent Model
Karim A Sarhane, MD, MSc1, Benjamin R Slavin, BS2, Nicholas Hricz, BS2, Harsha Malapati, BS2, Yi-nan Guo, BS1, Michael Grzelak, BS1, Irene Aran Chang, HSDG1, Alison L Wong, MD, MSE1, Ruifa Mi, MD, PhD1, Ahmet Höke, MD, PhD1 and Sami H. Tuffaha, MD3, (1)Johns Hopkins University, Baltimore, MD, (2)Johns Hopkins University School of Medicine, Baltimore, MD, (3)Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
Background: Functional recovery following peripheral nerve injury worsens with increasing duration of delay prior to nerve repair. Until reinnervation occurs, denervated muscle undergoes progressive atrophy that limits the extent to which motor function can be restored. Similarly, Schwann cells (SC) in the distal nerve undergo denervation atrophy that hinders their capacity to support regenerating axons. The relative contributions of these processes to diminished functional recovery is unclear.
Methods: We developed a novel rat model that isolates the effects of distal nerve vs. muscle denervation on functional recovery with four groups (Figure 1A) that underwent the following interventions for 12 weeks prior to nerve repair: 1) muscle denervation; 2) nerve/SC denervation; 3) muscle + nerve/SC denervation (negative control); 4) no denervation (positive control). Functional recovery was measured weekly using stimulated grip strength testing. Animals were sacrificed at 12 weeks for histological analyses.
Results: The muscle denervation group achieved greater functional recovery than the nerve/SC denervation group. Functional recovery in the muscle denervation group and nerve/SC denervation group mirrored the negative and positive control groups, respectively (p<0.05), Figure 1B. Neuromuscular junction analysis and muscle histology confirmed these results (Figure 1C and 1D).
Conclusions: The deleterious effects of muscle denervation are more consequential than the effects Schwann cell denervation on functional recovery. The effects of 12 weeks of Schwann cell denervation on functional outcome were negligible. Future studies are needed to determine if greater periods of Schwann cell denervation negatively impact functional recovery.
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