TRPV1 and TRPV4 Play Pivotal Roles in Delayed Onset Muscle Soreness

Hiroki Ota,Makoto Tominaga,Kazue Mizumura,Makiko Kashio,Shiori Murase,Kimiaki Katanosaka,Masabumi Minami

doi:10.1371/journal.pone.0065751

Abstract

Unaccustomed strenuous exercise that includes lengthening contraction (LC) often causes tenderness and movement related pain after some delay (delayed-onset muscle soreness, DOMS). We previously demonstrated that nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) are up-regulated in exercised muscle through up-regulation of cyclooxygenase (COX)-2, and they sensitized nociceptors resulting in mechanical hyperalgesia. There is also a study showing that transient receptor potential (TRP) ion channels are involved in DOMS. Here we examined whether and how TRPV1 and/or TRPV4 are involved in DOMS. We firstly evaluated a method to measure the mechanical withdrawal threshold of the deep tissues in wild-type (WT) mice with a modified Randall-Selitto apparatus. WT, TRPV1−/− and TRPV4−/− mice were then subjected to LC. Another group of mice received injection of murine NGF-2.5S or GDNF to the lateral gastrocnemius (LGC) muscle. Before and after these treatments the mechanical withdrawal threshold of LGC was evaluated. The change in expression of NGF, GDNF and COX-2 mRNA in the muscle was examined using real-time RT-PCR. In WT mice, mechanical hyperalgesia was observed 6–24 h after LC and 1–24 h after NGF and GDNF injection. LC induced mechanical hyperalgesia neither in TRPV1−/− nor in TRPV4−/− mice. NGF injection induced mechanical hyperalgesia in WT and TRPV4−/− mice but not in TRPV1−/− mice. GDNF injection induced mechanical hyperalgesia in WT but neither in TRPV1−/− nor in TRPV4−/− mice. Expression of NGF and COX-2 mRNA was significantly increased 3 h after LC in all genotypes. However, GDNF mRNA did not increase in TRPV4−/− mice. These results suggest that TRPV1 contributes to DOMS downstream (possibly at nociceptors) of NGF and GDNF, while TRPV4 is located downstream of GDNF and possibly also in the process of GDNF up-regulation.

Highlights

Delayed-onset muscle soreness (DOMS) is described as unpleasant sensation or tenderness after unaccustomed strenuous exercise [1]
No change was observed in the vehicle group (Fig. 3B). These results suggest that TRPV4 is involved in the mechanical hyperalgesia after lengthening contraction (LC)
In contrast to WT, the withdrawal threshold in TRPV12/2 and TRPV42/2 mice did not decrease after glial cell line-derived neurotrophic factor (GDNF) injection (Fig. 7). These results demonstrate that GDNF, which is up-regulated in the skeletal muscle to nerve growth factor (NGF), induces mechanical hyperalgesia through both TRPV1 and TRPV4 activation

Summary

Introduction

Delayed-onset muscle soreness (DOMS) is described as unpleasant sensation or tenderness after unaccustomed strenuous exercise [1]. In humans, it usually appears after some delay (up to 1–2 days), and disappears naturally within 3–7 days [1,2]. A model using lengthening contraction (LC) and a method for evaluating muscular mechanical hyperalgesia (tenderness) in rats have been developed [3] Using these tools, two pathways for generating DOMS have been demonstrated: One is from bradykinin-like substance (arg-bradykinin in rats) to nerve growth factor (NGF) [4] and the other is from COX-2 to glial cell line-derived neurotrophic factor (GDNF) [5]. Similar to NGF, GDNF works as a trophic factor for a subgroup of developing sensory neurons in fetal life [13] and is involved in several pain states in adult animals, but its effects are either analgesic [14,15] or hyperalgesic [16]

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