Physical Activity Modulates Nerve Plasticity and Stimulates Repair after Achilles Tendon Rupture Daniel K-I. Bring, Andris Kreicbergs, Per A.F.H. Renstrom, Paul W. Ackermann Section of Orthopaedics and Sports Medicine, Department of Molecular Medicine and Surgery, Karolinska Institutet, Research Center M3:00, Karolinska Hospital, S-171 76 Stockholm, Sweden Received 22 November 2005; accepted 11 May 2006 Published online 26 October 2006 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jor.20257 ABSTRACT: In a rat model of tendon rupture using semiquantitative methodology, healing was assessed according to the diameter of newly organized collagen and the occurrence of the sensory neuropeptides (SP, CGRP) in relation to different levels of physical activity. Normally, innervation of the Achilles tendon is confined to the paratenon. After rupture new nerve fibers grow into the tendon proper, but disappear after healing. In a first experiment to establish peak tissue and nerve regeneration after rupture, tendon tissues from freely moving rats were collected consecutively over 16 weeks. A peak increase in organized collagen and nerve ingrowth was observed between week 2 to 4 post rupture. Therefore, in a second experiment week 4 was chosen to assess the effect of physical activity on tendon healing in three groups of rats, that is, wheel running, plaster treated, and freely moving (controls). In the wheel-running group, the diameter of newly organized collagen was 94% ( p ¼ 0.001) greater than that in the plaster-treated group and 48% ( p ¼ 0.02) greater than that in the controls. Inversely, the neuronal occurrence of CGRP in the tendon proper was 57% ( p ¼ 0.02) lower in the wheel-running group than that in the plaster-treated group and 53% ( p ¼ 0.02) lower than that in the controls, suggesting an earlier neuronal in-growth and disappearance in the more active group. Physical activity speeds up tendon healing, which may prove to be linked to accelerated neuronal plasticity. ß 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:164–172, 2007 Keywords: Achilles tendon; healing; physical activity; nerves; sensory neuropeptides INTRODUCTION It is well known that repair of tendons is associated with a protracted healing process and suboptimal functional outcome. 1–5 During the past decade early mobilization and exercise have been shown to promote tissue repair after injury to the locomotor apparatus. 6–9 The underlying mechanisms have been studied extensively, but still remain largely unknown. Over the last years, it has been suggested that so-called neuropeptides play an important regula- tory role in tissue repair and homeostasis. 10,21,26 Recently, we reported that ruptured tendons during the early regenerative phase of healing (weeks 1–4) exhibit intense new nerve fiber ingrowth into the proper tendon, otherwise devoid of nerves fibers. 10 We also noted that nerve ingrowth was characterized by a specific temporal occurrence of sensory neuropeptides. 11 The two sensory neuropeptides analyzed, that is, substance P (SP) and calcitonine gene related peptide (CGRP), have previously been reported to promote angiogenesis and tissue regeneration, 12,13,15,16,23,26 partly by stimulating proliferation of endothelial cells and fibroblasts. 12,13,23,24 Given that neuropeptides mediate trophic effects, it might prove that the positive effects seen after mechanical stimulation, that is, early mobi- lization and exercise after tendon injury, is mediated to some extent by the peripheral nervous system. The current study on Achilles tendon rupture was designed to investigate healing and the occurrence of sensory neuropeptides in relation to physical activity. MATERIALS AND METHODS The current study entailed two parts. Part 1 was a longitudinal experiment with a duration of 16 weeks after tendon rupture (in part published elsewhere, data published here with the kind approval of The Ortho- paedic Research Society; reprinted from Ackermann PW, Li J, Lundeberg T, et al. Neuronal plasticity in 164 JOURNAL OF ORTHOPAEDIC RESEARCH FEBRUARY 2007 Correspondence to: Daniel Bring (Telephone: þ46-8-517 70531; Fax: þ46-8-333183; E-mail: Daniel.Bring@ki.se) ß 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.