Introduction: Peripheral nerve injury is associated with trauma and is often amenable to surgery. Functional recovery remains a challenging clinical problem that often leads to significant morbidity. Therapies that augment surgical repair may be beneficial in functional outcomes. Macrophages are responsible for the breakdown of debris following injury as well as promotion of regenerative signals. Macrophage polarization is the process by which macrophages take on phenotypically distinct functions based on the local environment and signaling cues. Exercise has been shown to drive macrophage polarization from a pro-inflammatory M1 phenotype towards an anti-inflammatory M2 phenotype in numerous tissues, but remains uninvestigated in the peripheral nervous system (1,2,3).
Methods: The purpose of our study was to identify how exercise affects macrophage polarization, motor and sensory function, and neuroregeneration following sciatic nerve crush. Male and female C57BL/6 mice underwent sciatic nerve crush injury and were then given access to running wheels (exercised) or not given access to running wheels (sedentary) for 4 weeks. Analysis included behavioral assessments, anatomical studies, and in vitro studies.
Results: Exercised mice ran an average of 2.9 km per night. Injured exercised mice were protected from the development of thermal hyperalgesia. Exercised mice had fewer paw slips on beam walk testing compared to sedentary mice. No differences were measured in mechanical sensitivity or motor coordination and balance. Motor nerve conduction velocities from injured exercised animals were significantly higher than injured sedentary animals suggesting improved nerve recovery with exercise. Injured sciatic nerves from exercised mice demonstrated increased M2 macrophages compared to sciatic nerves from injured sedentary mice. The behavioral changes and altered macrophage polarization correlated with increased epidermal nerve fiber density, improved myelination, and increased in vitro neurite outgrowth from injured exercised animals.
Conclusions: Exercise alters macrophage polarization towards an anti-inflammatory phenotype which improves repair and recovery of the injured peripheral nerve.
Patient Care: This research provides data suggesting exercise, in conjunction with surgery, may be used as a therapy to improve functional recovery and nerve regeneration following peripheral nerve injury
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of exercise following peripheral nerve injury. 2) Discuss the basics of macrophage polarization and how exercise effects this process following sciatic nerve injury. 3) Identify functional testing and measures of peripheral nerve regeneration following exercise treatment.
References: 1. Kawanishi, N., H. Yano, Y. Yokogawa and K. Suzuki (2010). "Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice." Exerc Immunol Rev 16: 105-118.
2. Oliveira, A. G., T. G. Araujo, B. M. Carvalho, D. Guadagnini, G. Z. Rocha, R. A. Bagarolli, J. B. Carvalheira and M. J. Saad (2013). "Acute exercise induces a phenotypic switch in adipose tissue macrophage polarization in diet-induced obese rats." Obesity (Silver Spring) 21(12): 2545-2556.
3. Silveira, L. S., M. Antunes Bde, A. L. Minari, R. V. Dos Santos, J. C. Neto and F. S. Lira (2016). "Macrophage Polarization: Implications on Metabolic Diseases and the Role of Exercise." Crit Rev Eukaryot Gene Expr 26(2): 115-132.