Pre-Injury Exercise Attenuates Lymphedema Induced by Surgery and Radiation in a Mouse Hindlimb Model.

Abstract

BACKGROUND: Lymphedema is a common but distressing sequela after cancer treatment. A cure is not yet available; thus, prevention is essential in its management. METHODS AND RESULTS: Here, we used a mouse hindlimb model to demonstrate the effects of exercise performed before lymph node resection and irradiation on the development of lymphedema. BALB/c mice trained on a treadmill at moderate intensity, 30 minutes/day, 5 times/week for 4 weeks, were compared to a no-exercise group (= 7/group). Weekly limb measurements and indocyanine green (ICG) lymphangiography were performed to assess lymphedema severity. Pre-injury exercise mice consistently showed a lower percentage excess in ankle diameter, reflecting a lesser degree of swelling. Moreover, most of them exhibited the mild "splash" pattern on ICG lymphangiography, while some reverted to the normal linear pattern on the 3rd week. Meanwhile, most of the no-exercise mice displayed the moderate "stardust" and severe "diffuse" patterns throughout the observation period. Histopathological analysis revealed a lesser increase in skin thickness and a greater density of lymphatic vessels of the exercise mice. CONCLUSION: Taken together, results showed that pre-injury exercise attenuated the development of lymphedema in our mouse hindlimb model. This provides preliminary evidence on the potential preventive role of exercise in secondary lymphedema.