Effect of Treadmill Training on ERK-Mediated Schwann Cell Proliferation and Axonal Regrowth in the Regenerating Sciatic Nerves

Abstract

Proliferation of Schwann cells present in distal stump of injured sciatic nerve is a critical step for successful regeneration and this process is facilitated by physical activity. Extracellular signal-regulated kinase 1/2 (ERK1/2) regulates proliferation and differentiation of non-neuronal cells, but correlation between ERK1/2 activation and exercise remains mostly unknown. Here we show that phosphorylation of ERK1/2 (p-ERK1/2) mediates proliferation of Schwann cells at early stage after injury and treadmill training (TMT) is a key regulator for upreulation of p-ERK1/2 induction levels via activation of Schwann cells. Using primary cell culture techniques, we identified the positive effect of low- intensity TMT on neurite outgrowth of dorsal root ganglions (DRG) and proliferation of Schwann cells in normal rat. After sciatic nerve injury, TMT increased induction levels of GAP-43 protein, regeneration marker, according to the passage of TMT duration and sustained phosphorylation of ERK1/2 by 7 days after injury. Also transcription factor c-Jun related with MAPK was observed in injured nerve at 3 days post crush and largely upregulated by daily TMT performance. p-ERK1/2 protein expressed in Schwann cells was distally transported and accelerated by TMT at 1 and 3 days post crush. We further demonstrate that TMT promoted axonal regeneration 3 days after sciatic nerve injury, greatly suppressed by in vivo administration of ERK kinase inhibitor PD98059. Thus, the present data provide a new evidence that TMT-mediated enhancement of axonal regeneration involves dynamic regulation of Schwann cell activity by phosphorylation of ERK1/2.