Sciences of Motricity Institute, Federal University of Alfenas, Alfenas, Brazil.
Department of Pharmacology, University of São Paulo, Ribeirão Preto, Brazil.
J Neurochem. 2020 Oct;155(1):29-44. doi: 10.1111/jnc.15006. Epub 2020 May 22.
Delayed-onset muscle soreness (DOMS) is a very common condition in athletes and individuals not accustomed to physical activity that occurs after moderate/high-intensity exercise sessions. The activation of microglial Toll-like receptor 4 (TLR4) in the spinal cord has been described to be important for the induction and maintenance of persistent pain. Based on that, we hypothesize that 70 kilodalton heat-shock protein (Hsp70), a mediator released by exercise, could activate microglial TLR4 in the spinal cord, releasing proinflammatory cytokines and contributing to the start of DOMS. In fact, we found that the knockout of TLR4, myeloid differentiation primary response 88 (MyD88), interleukin-6 (IL-6), or both tumor necrosis factor-α (TNF-α) receptor 1 and TNF-α receptor 2 in mice prevented the development of DOMS following acute aerobic exercise in contrast to the findings in male C57BL/6 wild-type mice. Furthermore, DOMS in exercised wild-type mice was also prevented after pre-treatment with microglia inhibitor, TLR4 antagonist, and anti-Hsp70 antibody. During exercise-induced DOMS, Hsp70 mRNA, TLR4 mRNA, and protein levels, as well as Iba-1 (a microglial marker), IL-6, and TNF-α protein levels, were increased in the muscle and/or spinal cord. Together, these findings suggest that Hsp70 released during exercise-induced DOMS activates the microglial TLR4/IL-6/TNF-α pathway in the spinal cord. Thus, the blockade of TLR4 activation may be a new strategy to prevent the development of DOMS before intense exercise.
延迟性肌肉酸痛（DOMS）是运动员和不习惯体力活动的个体在中等/高强度运动后非常常见的一种情况。脊髓中小胶质细胞 Toll 样受体 4（TLR4）的激活被描述为诱导和维持持续性疼痛的重要因素。基于这一点，我们假设 70 千道尔顿热休克蛋白（Hsp70），一种运动释放的介质，可能会激活脊髓中的小胶质细胞 TLR4，释放促炎细胞因子，导致 DOMS 的开始。事实上，我们发现 TLR4、髓样分化初级反应 88（MyD88）、白细胞介素-6（IL-6）或 TNF-α 受体 1 和 TNF-α 受体 2 的敲除可预防急性有氧运动后 DOMS 的发展与 C57BL/6 野生型雄性小鼠的发现相反。此外，在运动后用小胶质细胞抑制剂、TLR4 拮抗剂和抗 Hsp70 抗体预处理也可预防野生型小鼠的 DOMS。在运动引起的 DOMS 期间，肌肉和/或脊髓中的 Hsp70 mRNA、TLR4 mRNA 和蛋白水平以及 Iba-1（小胶质细胞标志物）、IL-6 和 TNF-α 蛋白水平增加。总之，这些发现表明，运动引起的 DOMS 期间释放的 Hsp70 激活了脊髓中的小胶质细胞 TLR4/IL-6/TNF-α 通路。因此，阻断 TLR4 激活可能是在剧烈运动前预防 DOMS 发展的一种新策略。
