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expressing BDNF (
Wilhelm et al., 2012
). However, in animals normally
expressing BDNF, treadmill exercise was capable of enhancing axonal elon-
gation even through nerve grafts void of this neurotrophin (
Wilhelm et al.,
2012
). Likewise, NT-4/5 expression within the regenerating nerve is
required for treadmill running to enhance axonal growth (
English,
Cucoranu, et al., 2011; English, Wilhelm, et al., 2011
). In NT-4/5 knock-
out mice, treadmill running is unable to alter the rate at which axons grow
along the common fibular nerve. However, nerve grafts from NT-4/5
knockout donors or acellular nerve grafts do not cancel the role played
by treadmill running in stimulating axonal growth, thereby indicating that
the NT-4/5 acts in the proximal nerve stump, most likely at the level of the
regenerating neurons (
English, Cucoranu, et al., 2011; English, Wilhelm,
et al., 2011
).
2.2.3 Improving the nerve regenerative environment
The distal nerve pathway plays a key role in sustaining peripheral nerve
regeneration. Schwann cells provide guidance to regenerating axons
(
Allodi, Udina, & Navarro, 2012
), and prolonged denervation of the distal
nerve stump is a major reason for impaired reinnervation of target organs
(
Gordon et al., 2011; H¨ke & Brushart, 2010
). Only few studies exist relat-
ing physical exercise and Schwann cell function in axotomized peripheral
nerves.
Seo et al. (2006)
reported that treadmill exercise, undertaken during
the initial 14 days after sciatic nerve injury, improves sciatic nerve regener-
ation and functional recovery. In this case, treadmill exercise increased the
levels of cell division cycle 2 (cdc2) mRNA and protein at the injury site.
This marker of tissue regeneration colocalized with the Schwann cell marker
S100 beta protein, and treatment with a cdc2 antagonist counteracted the
effect of treadmill exercise in improving nerve regeneration (
Seo et al.,
2006
). In a sequence study, mild-intensity treadmill exercise also stimulated
Schwann cell proliferation following sciatic nerve injury in the rat via
increase of extracellular regulated kinase (Erk) 1/2 activity. In this study,
phosphorylated Erk1/2 upregulation in Schwann cells followed the increase
of growth-associated protein (GAP)-43 mRNA and protein levels in the sci-
atic nerve, as well as the increase of the phosphorylated form of the down-
stream effector c-Jun (
Seo et al., 2009
). Another sort of mechanisms
that may promote Schwann cell function is related with preventing cell apo-
ptosis in the distal nerve. In a study undertaken by
Shokouhi et al. (2008)
,
treadmill running exerted a protective effect against lipid peroxidation in
intact nerves, thus reducing Schwann cell apoptosis. A further potential
