Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat.
ABSTRACT: Delayed-onset muscle soreness is typically observed after strenuous or unaccustomed eccentric exercise. Soon after recovery, blunted muscle soreness is observed on repeated eccentric exercise, a phenomenon known as repeated bout effect (RBE). Although regular physical activity decreases muscle hyperalgesia, likely because of increased production of the anti-inflammatory cytokine interleukin-10 (IL-10) in the skeletal muscle, whether IL-10 also contributes to the antinociceptive effect of RBE is unknown. Furthermore, whether IL-10 attenuates muscle hyperalgesia by acting on muscle nociceptors remains to be established. Here, we explored the hypothesis that blunted muscle nociception observed in RBE depends on a local effect of IL-10, acting on IL-10 receptor 1 (IL-10R1) expressed by muscle nociceptors. Results show that after a second bout of eccentric exercise, rats exhibited decreased muscle hyperalgesia, indicative of RBE, and increased expression of IL-10 in the exercised gastrocnemius muscle. Although knockdown of IL-10R1 protein in nociceptors innervating the gastrocnemius muscle by intrathecal antisense oligodeoxynucleotide did not change nociceptive threshold in naive rats, it unveiled latent muscle hyperalgesia in rats submitted to eccentric exercise 12 days ago. Furthermore, antisense also prevented the reduction of muscle hyperalgesia observed after a second bout of eccentric exercise. These data indicate that recovery of nociceptive threshold after eccentric exercise and RBE-induced analgesia depend on a local effect of IL-10, acting on its canonical receptor in muscle nociceptors.
Project description:Introduction:Although stress is a well-establish risk factor for the development of chronic musculoskeletal pain, the underlying mechanisms, specifically the contribution of neuroendocrine stress axes, remain poorly understood. Objective:To evaluate the hypothesis that psychological stress-induced activation of the sympathoadrenal stress axis prolongs the muscle pain observed after strenuous exercise. Methods:Adult male Sprague-Dawley rats were exposed to unpredictable sound stress and eccentric exercise. The involvement of the sympathoadrenal stress axis was evaluated by means of surgical interventions, systemic administration of epinephrine, and intrathecal ?2-adrenergic receptor antisense. Results:Although sound stress alone did not modify nociceptive threshold, it prolonged eccentric exercise-induced mechanical hyperalgesia. Adrenal medullectomy (ADMdX) attenuated, and administration of stress levels of epinephrine to ADMdX rats mimicked this effect of sound stress. Knockdown of ?2-adrenergic receptors by intrathecal antisense also attenuated sound stress-induced prolongation of eccentric exercise-induced hyperalgesia. Conclusion:Together, these results indicate that sympathoadrenal activation, by unpredictable sound stress, disrupts the capacity of nociceptors to sense recovery from eccentric exercise, leading to the prolongation of muscle hyperalgesia. This prolonged recovery from ergonomic pain is due, at least in part, to the activation of ?2-adrenergic receptors on muscle nociceptors.
Project description:Eccentric exercise results in an adaptation which attenuates muscle damage from subsequent exercise-termed the "repeated-bout effect (RBE)."Study examined antagonist co-activation and motor-unit recruitment strategy, assessed via dEMG, concomitant to the RBE.Nine participants performed 5 sub-maximal isometric trapezoid (ramp-up, hold, ramp-down) contractions at force levels corresponding to 50% and 80% of maximal isometric strength (MVC). Surface EMG signals of the biceps brachii were decomposed into individual motor-unit action potential trains. The relationship between mean firing rate (MFR) of each motor-unit and its recruitment threshold (RT) was examined using linear regression. Eccentric exercise was then performed until biceps brachii MVC had decreased by ~40%. Surface EMG of the biceps and triceps were collected during eccentric exercise. MVC, range-of-motion (ROM), and delayed onset muscle soreness (DOMS) were measured 24-hours, 72-hours, and 1-week following eccentric exercise. Three weeks later all procedures were repeated.Changes in MVC (-32±14% vs -25±10%; p = 0.034), ROM (-11% vs 6%; p = 0.01), and DOMS (31.0±19mm vs 19±12mm; p = 0.015) were attenuated following the second bout of exercise. Triceps EMG was reduced (16.8±9.5% vs. 12.6±7.2%; p = 0.03) during the second bout of eccentric exercise. The slope (-0.60±0.13 vs -0.70±0.18; p = 0.029) and y-intercept (46.5±8.3 vs 53.3±8.8; p = 0.020) of the MFR vs. RT relationship was altered during contractions at 80% of MVC prior to the second bout of eccentric exercise. No changes were observed at 50% of MVC.A reduction in antagonist co-activation during the second bout of eccentric exercise suggests less total force was required to move an identical external load. This finding is supported by the increased negative slope coefficient and an increased y-intercept of the linear relationship between RT and MFR.
Project description:Eccentric muscle exercise is a common cause of acute and chronic (lasting days to weeks) musculoskeletal pain. To evaluate the mechanisms involved, we have employed a model in the rat, in which eccentric hind limb exercise produces both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to subsequent exposure to an inflammatory mediator. Eccentric exercise of the hind limb produced mechanical hyperalgesia, measured in the gastrocnemius muscle, which returned to baseline at 120 h post-exercise. When nociceptive thresholds had returned to baseline, intramuscular injection of prostaglandin E(2) (PGE(2) ) induced hyperalgesia that was unattenuated 240 h later, much longer than PGE(2) -induced hyperalgesia in unexercised rats (4 h). This marked prolongation of PGE(2) hyperalgesia induced by eccentric exercise was prevented by the spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase C?, a second messenger in nociceptors implicated in the induction of chronic pain. Exercise-induced hyperalgesia and prolongation of PGE(2) hyperalgesia were inhibited by the spinal intrathecal administration of antisense for the interleukin-6 but not the tumor necrosis factor ? type 1 receptor. These findings provide further insight into the mechanism underlying exercise-induced chronic muscle pain, and suggest novel approaches for the prevention and treatment of exercise- or work-related chronic musculoskeletal pain syndromes.
Project description:The current consensus in exercise physiology is that the repeated bout effect always appears after few eccentric exercise sessions. This is the first attempt to challenge this tenet, by exploiting specificity in muscle plasticity. More specifically, we examined whether the opposing adaptations in muscle induced after concentric and eccentric exercise can attenuate and/or remove the repeated bout effect. Seventeen young men were randomly assigned into one of the following groups: (1) the alternating eccentric-concentric exercise group; and (2) the eccentric-only exercise group. Both groups performed 8 weeks of resistance exercise using the knee extensors of both legs on an isokinetic dynamometer. The alternating eccentric-concentric exercise group performed an alternating exercise protocol, switching between eccentric-only and concentric-only exercise every 4 weeks, while the eccentric-only group performed eccentric exercise. Evaluation of muscle damage using physiological (isometric torque, delayed onset muscle soreness, and range of movement) and biochemical (creatine kinase) markers and inflammation (C-reactive protein) was performed at weeks 1, 5, and 10. Baseline isometric peak torque was also evaluated at week 14 after another cycle (4 weeks) of alternating or eccentric-only exercise training. In the alternating eccentric-concentric exercise group, the concentric exercise training performed prior to eccentric exercise reduced dramatically the repeated bout effect by reversing muscle back to its unaccustomed state. On the contrary, the eccentric-only exercise group exhibited a typical manifestation of the repeated bout effect. Interestingly, muscle strength was elevated similarly for both alternating and eccentric-only exercise groups after 13 weeks of training. The alternating eccentric-concentric exercise scheme, implemented in the present study, has for the first time successfully overcame the repeated bout effect. The similarity in muscle strength measurements following the two protocols is against the notion that inflammation plays an important role in exercise-induced adaptations in muscle.
Project description:10 male subjects performed ~45 min one-legged cycling and 4 x 7 maximal concentric-eccentric knee extensions for each leg 15 min later. Thus, one limb performed aerobic and resistance exercise (AE+RE), while the opposing leg did resistance exercise only (RE). Biopsies were obtained from m. vastus lateralis of each leg 3 h after the resistance exercise bout. Gene expression analysis was carried out on the Affymetrix HuGene-2.1-st platform. Overall design: Skeletal muscle gene expression after a single bout of one-legged resistance type exercise only or one bout of one-legged resistance type exercise combined with one bout of aerobic exercise
Project description:Unaccustomed eccentric exercise is accompanied by muscle damage and impaired glucose uptake and glycogen synthesis during subsequent recovery. Recently, it was shown that the role and regulation of glycogen in skeletal muscle are dependent on its subcellular localization, and that glycogen synthesis, as described by the product of glycogen particle size and number, is dependent on the time course of recovery after exercise and carbohydrate availability. In the present study, we investigated the subcellular distribution of glycogen in fibers with high (type I) and low (type II) mitochondrial content during post-exercise recovery from eccentric contractions. Analysis was completed on five male subjects performing an exercise bout consisting of 15 x 10 maximal eccentric contractions. Carbohydrate-rich drinks were subsequently ingested throughout a 48 h recovery period and muscle biopsies for analysis included time points 3, 24 and 48 h post exercise from the exercising leg, whereas biopsies corresponding to prior to and at 48 h after the exercise bout were collected from the non-exercising, control leg. Quantitative imaging by transmission electron microscopy revealed an early (post 3 and 24 h) enhanced storage of intramyofibrillar glycogen (defined as glycogen particles located within the myofibrils) of type I fibers, which was associated with an increase in the number of particles. In contrast, late in recovery (post 48 h), intermyofibrillar, intramyofibrillar and subsarcolemmal glycogen in both type I and II fibers were lower in the exercise leg compared with the control leg, and this was associated with a smaller size of the glycogen particles. We conclude that in the carbohydrate-supplemented state, the effect of eccentric contractions on glycogen metabolism depends on the subcellular localization, muscle fiber's oxidative capacity, and the time course of recovery. The early enhanced storage of intramyofibrillar glycogen after the eccentric contractions may entail important implications for muscle function and fatigue resistance.
Project description:BACKGROUND:Single bouts of muscle damaging eccentric exercise (EE) affect glucose metabolism negatively while single bouts of concentric (CE) and not muscle damaging eccentric exercise have positive acute short-term effects on glucose metabolism. It has been proposed that long-term endurance EE might be more effective in improving glucose metabolism than long-term CE when adjusted for energy expenditure. This would imply that adaptations of glucose metabolism are dependent on the type of exercise. Interleukin-6 (IL-6) released from the exercising muscles may be involved in and could therefore explain acute adaptations on glucose metabolism. The aim of the study was to investigate the effects of a single bout of CE and a single bout of EE inducing no or just mild muscle damage, matched for energy expenditure, on glucose metabolism. METHODS:7 healthy but sedentary female participants (age 20.7 ± 2.9 years; BMI 22.45 ± 1.66 kg m(-2); VO2peak 39.0 ± 4.5 ml kg(-1) min(-1)) took part in a randomized cross over trial consisting of 1 h uphill (CE) respectively downhill (EE) walking on a treadmill. Venous blood samples were drawn before, directly after and 24 h after exercise. An oral glucose tolerance test (OGTT) was performed before and 24 h after exercise. RESULTS:CE and EE lead to comparable changes of glucose tolerance (area under the curve of the OGTT) (-16.0 ± 25.81 vs. -6.3 ± 45.26 mg dl(-1) h(-1), p = 1.000) and HOMA insulin resistance (-0.16 ± 1.53 vs. -0.08 ± 0.75, p = 0.753). Compared to baseline, IL-6 concentration increased significantly immediately after EE (1.07 ± 0.67 vs. 1.32 ± 0.60 pg ml(-1), p = 0.028) and tended to increase immediately after CE (0.75 ± 0.29 vs. 1.03 ± 0.21 pg ml(-1), p = 0.058). TNF-? concentration decreased significantly immediately after EE (1.47 ± 0.19 vs. 1.06 ± 0.29 pg ml(-1), p = 0.046) but not after CE (1.27 ± 0.43 vs. 1.24 ± 0.43 pg ml(-1), p = 0.686) compared to baseline. CONCLUSIONS:Acute effects of a single bout of exercise inducing no or just mild muscle damage on glucose tolerance and insulin resistance seem to be primarily energy expenditure dependent whereas acute anti-inflammatory activity induced by a single bout of exercise appears to be rather exercise type dependent. TRIAL REGISTRATION:NCT01890876, clinicaltrials.gov, https://clinicaltrials.gov/.
Project description:Background: We have previously shown an accelerated recovery from muscle fatigue in men challenged by prolonged exercise after oral deep ocean minerals (DOM) supplementation. Here, we hypothesized a decrease in eccentric exercise-induced muscle inflammation in rats regularly consuming DOM-containing drinks (hardness 600 mg/L and fructose 11%). Methods: Forty-seven male Sprague Dawley rats were randomized into 4 groups: Control (C, N = 12), Fructose (F, N = 12), Fructose+Exercise (FE, N = 12), and Fructose+Exercise+DOM (FED, N = 11). Since fructose is a commonly used ingredient in beverages, 11% of fructose was added as a vehicle of the study. Soleus muscles of rats were analyzed 24 h after an acute bout of downhill running following 9 weeks of DOM supplementation. Results: Leukocyte infiltration and TNF-? mRNA of muscle in the FE group were 5 times and 4 times greater the F group, respectively, (P < 0.05). Both markers in the FED group were significantly lower than those in the FE group (P < 0.05). IL-10 mRNA of muscle in the F group was >eight fold greater than the C group (P < 0.05). The reduced glutathione (GSH) of muscle in the F group was 34% lower than that in the C group (P < 0.05). However, GSH levels were similar for the C and FED groups. Conclusion: Prolonged fructose supplementation modulates inflammatory balance of rat skeletal muscle. The results of the study suggest that DOM can minimize eccentric exercise-induced inflammatory cytokine responses in rat skeletal muscle.
Project description:Eccentric contractions produce a significant degree of inflammation and muscle injury that may increase the expression of myostatin. Due to its anti- oxidant and anti-flammatory effects, circulating 17-? estradiol (E2) may attenuate myostatin expression. Eight males and eight females performed 7 sets of 10 reps of eccentric contractions of the knee extensors at 150% 1-RM. Each female performed the eccentric exercise bout on a day that fell within her mid-luteal phase (d 21-23 of her 28-d cycle). Blood and muscle samples were obtained before and 6 and 24 h after exercise, while additional blood samples were obtained at 48 and 72 h after exercise. Serum E2 and myostatin LAP/propeptide (LAP/pro) levels were determined with ELISA, and myostatin mRNA expression determined using RT-PCR. Data were analyzed with two-way ANOVA and bivariate correlations (p < 0.05). Females had greater levels of serum E2 throughout the 72- h sampling period (p < 0.05). While males had greater body mass and fat-free mass, neither was correlated to the pre-exercise levels of myostatin mRNA and LAP/pro for either gender (p > 0.05). Compared to pre-exercise, males had significant increases (p < 0.05) in LAP/propetide and mRNA of 78% and 28%, respectively, at 24 h post-exercise, whereas females underwent respective decreases of 10% and 21%. E2 and LAP/propeptide were correlated at 6 h (r = -0.804, p = 0.016) and 24 h post- exercise (r = -0.841, p = 0.009) in males, whereas in females E2 levels were correlated to myostatin mRNA at 6 h (r =0.739, p = 0.036) and 24 h (r = 0.813, p = 0.014) post-exercise and LAP/propeptide at 6 h (r = 0.713, p = 0.047) and 24 h (r = 0.735, p = 0.038). In females, myostatin mRNA expression and serum LAP/propeptide levels do not appear to be significantly up-regulated following eccentric exercise, and may be due to higher levels of circulating E2. Key PointsThe pre-exercise levels of myostatin mRNA and propeptide were not significantly different between genders, and even though the total body mass and fat-free mass of males were significantly greater than females, neither was correlated to myostatin mRNA or LAP/propeptide.Myostatin mRNA expression in females is less than in males 24 h after a single bout of eccentric exercise.Myostatin LAP/propeptide levels in females are lower in females than in males 24 h after a single bout of eccentric exercise, thereby suggesting a gender-specific mechanism in which females may be less responsive to eccentric exercise than males.Myostatin mRNA expression in females is attenuated, possibly due to inhibition in myostatin signaling, and appears to be more related to the presence of a higher level of circulating E2 rather than body composition.Due to their higher level of E2, females seem to be less susceptible to the mechanism by which eccentric exercise apparently up-regulates myostatin mRNA expression in males.
Project description:Chronic muscle pain is a prominent symptom of the hand-arm vibration syndrome (HAVS), an occupational disease induced by exposure to vibrating power tools, but the underlying mechanism remains unknown. We evaluated the hypothesis that vibration induces an interleukin 6 (IL-6)-mediated downregulation of the potassium voltage-gated channel subfamily A member 4 (KV1.4) in nociceptors leading to muscle pain. Adult male rats were submitted to a protocol of mechanical vibration of the right hind limb. Twenty-four hours after vibration, muscle hyperalgesia was observed, concomitant to increased levels of IL-6 in the gastrocnemius muscle and decreased expression of KV1.4 in the dorsal root ganglia. Local injection of neutralizing antibodies against IL-6 attenuated the muscle hyperalgesia induced by vibration, whereas antisense knockdown of this channel in the dorsal root ganglia mimicked the muscle hyperalgesia observed in the model of HAVS. Finally, knockdown of the IL-6 receptor signaling subunit glycoprotein 130 (gp130) attenuated both vibration-induced muscle hyperalgesia and downregulation of KV1.4. These results support the hypothesis that IL-6 plays a central role in the induction of muscle pain in HAVS. This likely occurs through intracellular signaling downstream to the IL-6 receptor subunit gp130, which decreases the expression of KV1.4 in nociceptors.