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Review
. 2016 Jan;66(1):43-52.
doi: 10.1007/s12576-015-0397-0.

Delayed onset muscle soreness: Involvement of neurotrophic factors

Kazue Mizumura, Toru Taguchi
Review

Delayed onset muscle soreness: Involvement of neurotrophic factors

Kazue Mizumura et al. J Physiol Sci. 2016 Jan.

Abstract

Delayed-onset muscle soreness (DOMS) is quite a common consequence of unaccustomed strenuous exercise, especially exercise containing eccentric contraction (lengthening contraction, LC). Its typical sign is mechanical hyperalgesia (tenderness and movement related pain). Its cause has been commonly believed to be micro-damage of the muscle and subsequent inflammation. Here we present a brief historical overview of the damage-inflammation theory followed by a discussion of our new findings. Different from previous observations, we have observed mechanical hyperalgesia in rats 1-3 days after LC without any apparent microscopic damage of the muscle or signs of inflammation. With our model we have found that two pathways are involved in inducing mechanical hyperalgesia after LC: activation of the B2 bradykinin receptor-nerve growth factor (NGF) pathway and activation of the COX-2-glial cell line-derived neurotrophic factor (GDNF) pathway. These neurotrophic factors were produced by muscle fibers and/or satellite cells. This means that muscle fiber damage is not essential, although it is sufficient, for induction of DOMS, instead, NGF and GDNF produced by muscle fibers/satellite cells play crucial roles in DOMS.

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Figures

Fig. 1
Fig. 1
NGF involvement in DOMS. a NGF mRNA of the EDL was upregulated first 12 h after LC, and continued to be upregulated up to 2 days after LC. b NGF protein was also upregulated in a time course similar to that for mRNA. c Intramuscular injection of anti-NGF antibody reversed already established mechanical hyperalgesia in 3 h. Black filled circles, normal goat IgG injection group; grey filled squares, anti-NGF antibody injection group. Modified from Murase et al. [64]
Fig. 2
Fig. 2
NGF sensitized muscle C-fiber afferents to mechanical stimulation. a, b Sample recording of muscle C-fibers with intramuscular injection of phosphate-buffered saline (PBS) (a) and NGF (b). Upper right insets in a, b show the location of the receptive field of the fiber. The 1st and 3rd traces are raw recordings of the fiber, and the 2nd and 4th traces show readouts of the mechanical force applied to the receptive field. c Summary of the change in the mechanical threshold. The threshold of the PBS group at each time point was set as 100 %. White circles, PBS group; filled black circles, NGF group. d Summary of the change in the magnitude of the response (number of discharges induced by mechanical stimulation). The magnitude of the response of the PBS group at each time point was set as 100 %. NGF was injected at time 0. *p < 0.05, **p < 0.01 compared with the PBS group at each time point in both c, d. From Murase et al. [64]
Fig. 3
Fig. 3
GDNF upregulation in the muscle after LC. a GDNF mRNA of the EDL was upregulated 12 h–1 day after LC. b, c Expression of GDNF mRNA (white arrowheads) in EDL muscle 12 h after LC, shown by use of dark-field photomicrographs of in-situ hybridization histochemistry (oblique sections), was increased on the ipsilateral side (c) compared with the contralateral side (b). Scale bar 100 µm. d Bright-field photomicrograph (longitudinal section) at greater magnification shows in-situ hybridization signals for GDNF mRNA (black arrowhead) in the ipsilateral muscle. Scale bar 10 µm. Note that GDNF mRNA signals are observed around the nuclei of muscle cells and/or satellite cells. Modified from Murase et al. [47]
Fig. 4
Fig. 4
a GDNF sensitized muscle Aδ-fiber afferents to mechanical stimulation. The method of presentation is similar to Fig. 2. The black triangles in b represent the GDNF injection group. # p < 0.05, two-way ANOVA, **p < 0.01, ***p < 0.001, two-way ANOVA followed by Bonferroni’s multiple comparison test. Modified from Murase et al. [76]
Fig. 5
Fig. 5
Schematic diagram of the mechanism proposed for DOMS. The upper part of the figure in the shaded area was based on Boix et al. [59]. BK, bradykinin-like substance (Arg-bradykinin in rats); COX2, cyclooxygenase-2; PGs, prostaglandins; EP2, prostaglandin EP2 receptor; GDNF, glial cell line-derived neurotrophic factor; NGF, nerve growth factor; ASIC, acid sensing ion channel; TRPV1 and TRPV4 transient receptor potential vanilloids 1 and 4. Modified from Mizumura et al. [79]
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