좌골신경 재생 시 슈반세포의 이주와 재수초화 관련 요인들에 미치는 트레드밀 운동의 효과
Effect of Treadmill Training on Migration of Schwann Cells and Remyelination-Associated Factors During Sciatic Nerve Regeneration
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좌골신경 손상 후 슈반세포의 기능적 활동성 증가는 축삭 재생을 촉진시킨다. Cell division cycle 2(Cdc2)는 세포 주기(cell cycle)의 G2와 M 기에서 작용하는 원형적 cyclic-dependent kinase이고 Extracellular signal-regulated kinase 1/2(ERK1/2)는 손상 신호에 대한 세포의 반응을 조절한다. 그러나 재생하는 좌골신경의 슈반세포에서 이러한 단백질들의 역할과 운동에 의한 조절 기전은 연구가 부족한 실정이다. 그러므로 이 연구에서는 좌골신경 손상 후 트레드밀 운동이 슈반세포의 증식에 관여하는 Cdc2와 ERK1/2의 인산화(p-ERK1/2)를 증가시키고, 이러한 단백질의 증가가 슈반세포의 이주를 촉진시키는지를 확인하고자 하였다. 좌골신경 손상 1, 3, 7, 14, 21 그리고 28일 후 저강도 트레드밀 운동에 의한 Cdc2와 p-ERK1/2의 발현 양상을 확인하기 위해, 적출된 좌골신경은 western blot 분석을 사용한 결과 손상 7일 후, Cdc2와 p-ERK1/2의 발현은 비운동 그룹에 비해 트레드밀 운동 그룹에서 통계적으로 유의하게 증가하였다. 또한 트레드밀 운동은 생체외의 이주 실험에서 슈반세포의 이주를 촉진시켰다. 손상된 좌골신경의 원위부에서 재수초화의 진행 양상을 확인하기 위해 MBP(myelin basic protein) 항체를 이용한 면역형광 염색법을 수행한 결과 5mm 원위부에서, 재수초화 형성은 비운동 그룹보다 트레드밀 운동군에서 향상되었다. 이러한 결과들을 종합해 보면, 운동에 의한 원위부 슈반세포의 Cdc2와 p-ERK1/2 발현 증가는 재생의 마지막 단계인 재수초화와 밀접한 관련이 있다는 새로운 증거를 제시하고 있다.
Abstract
Increased functional activity of Schwann cells in the injured peripheral nerves is closely related with axonal regeneration, and physical activity in animal models with sciatic nerve injury has been shown to enhance nerve regeneration. Cell division cycle 2 (Cdc2) is a prototypical cyclin-dependent kinase that promotes G2-M phase transition in the cell cycle. Extracellular signal-regulated kinase 1/2 (ERK1/2) regulates neuronal responses to injury signal. In this research, we report that treadmill training (TMT) after sciatic nerve injury facilitates migration and remyelination of proliferating Schwann cells via the increases of Cdc2 and p-Erk1/2 (phosphorylated Erk1/2) protein levels. To investigate exercise-regulated Cdc2 and p-ERK1/2, sciatic nerves in all groups were analyzed using the western blotting method. Cdc2 and p-ERK1/2 were increased more in the TMT group than the sedentary group in the 7th day after injury. TMT also elevated migration of Schwann cells in vitro. We performed immunofluorescence staining with anti-MBP (myelin basic protein) antibody to identify remyelination. TMT increased the number of remyelinated axons in the region 5 mm distal to the injury site. Thus, the present data provide a new evidence that increased Cdc2 and p-ERK1/2 activity in proliferating Schwann cells may play an important role in exercise-mediated enhancement of axonal regeneration in the injured peripheral nerve.
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