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Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects.

ABSTRACT: What is the central question of this study? Can physiological concentrations of metabolite combinations evoke sensations of fatigue and pain when injected into skeletal muscle? If so, what sensations are evoked? What is the main finding and its importance? Low concentrations of protons, lactate and ATP evoked sensations related to fatigue. Higher concentrations of these metabolites evoked pain. Single metabolites evoked no sensations. This suggests that the combination of an ASIC receptor and a purinergic P2X receptor is required for signalling fatigue and pain. The results also suggest that two types of sensory neurons encode metabolites; one detects low concentrations of metabolites and signals sensations of fatigue, whereas the other detects higher levels of metabolites and signals ache and hot. The perception of fatigue is common in many disease states; however, the mechanisms of sensory muscle fatigue are not understood. In mice, rats and cats, muscle afferents signal metabolite production in skeletal muscle using a complex of ASIC, P2X and TRPV1 receptors. Endogenous muscle agonists for these receptors are combinations of protons, lactate and ATP. Here we applied physiological concentrations of these agonists to muscle interstitium in human subjects to determine whether this combination could activate sensations and, if so, to determine how the subjects described these sensations. Ten volunteers received infusions (0.2 ml over 30 s) containing protons, lactate and ATP under the fascia of a thumb muscle, abductor pollicis brevis. Infusion of individual metabolites at maximal amounts evoked no fatigue or pain. Metabolite combinations found in resting muscles (pH 7.4 + 300 nm ATP + 1 mm lactate) also evoked no sensation. The infusion of a metabolite combination found in muscle during moderate endurance exercise (pH 7.3 + 400 nm ATP + 5 mm lactate) produced significant fatigue sensations. Infusion of a metabolite combination associated with vigorous exercise (pH 7.2 + 500 nm ATP + 10 mm lactate) produced stronger sensations of fatigue and some ache. Higher levels of metabolites (as found with ischaemic exercise) caused more ache but no additional fatigue sensation. Thus, in a dose-dependent manner, intramuscular infusion of combinations of protons, lactate and ATP leads to fatigue sensation and eventually pain, probably through activation of ASIC, P2X and TRPV1 receptors. This is the first demonstration in humans that metabolites normally produced by exercise act in combination to activate sensory neurons that signal sensations of fatigue and muscle pain.

SUBMITTER: Pollak KA

PROVIDER: S-EPMC3946674 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects.

Pollak Kelly A KA Swenson Jeffrey D JD Vanhaitsma Timothy A TA Hughen Ronald W RW Jo Daehyun D White Andrea T AT Light Kathleen C KC Schweinhardt Petra P Amann Markus M Light Alan R AR

Experimental physiology 20131018 2

<h4>New findings</h4>What is the central question of this study? Can physiological concentrations of metabolite combinations evoke sensations of fatigue and pain when injected into skeletal muscle? If so, what sensations are evoked? What is the main finding and its importance? Low concentrations of protons, lactate and ATP evoked sensations related to fatigue. Higher concentrations of these metabolites evoked pain. Single metabolites evoked no sensations. This suggests that the combination of an ...[more]

PMID: 24142455

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Project description:BackgroundAttending towards pain is proposed as a key mechanism influencing the experience and chronification of pain. Persistent attention towards pain is proposed to drive poor outcomes in both adults and children with chronic pain. However, there are no validated self-report measures of pain-related attention for children.MethodsThe goals of this study were to adapt the Pain Vigilance and Awareness Questionnaire (PVAQ) for use in a child sample, to preliminary examine its psychometric properties, and to assess its utility over and above a measure of general attentional capacities. We adapted the language of the PVAQ to be more easily understood by children as young as 8 years. In a sample of 160 children (8-18 years) with chronic pain, we examined the factor structure, internal consistency and criterion validity of the PVAQ-C.ResultsThe PVAQ-C demonstrated excellent internal consistency (α = 0.92) and moderate-to-strong criterion validity. A one-factor structure best fit the data. Children who reported greater attention to pain also reported greater pain catastrophizing, fear of pain, avoidance of activities and poorer physical functioning. Pain-related attention remained a significant predictor of functioning while controlling for demographics, catastrophizing and fear-avoidance. Pain-related attention also significantly predicted child outcomes independent of the child's general attention control capacities, indicating added value of a pain-specific measure of attention.ConclusionsThe PVAQ-C shows strong indices of internal reliability and criterion validity, and indicates unique predictive utility. It will be important to study the role of pain-related attention in youth within developmental and functional-motivational frameworks.SignificancePain-related attention is proposed as a key factor influencing fear-avoidance outcomes in both adults and youth with chronic pain, yet no self-report measures of pain-related attention have been validated for children. This paper presents a child version of the Pain Vigilance and Awareness Questionnaire (PVAQ-C), which indicates strong internal consistency, criterion validity and unique predictive validity, and provides evidence to support the Fear-Avoidance Model in youth with chronic pain.

Project description:The quest for sustainable strategies aimed at increasing the bioactive properties of plant-based foods has grown quickly. In this work, we investigated the impact of exogenously applied phenolics, i.e., chlorogenic acid (CGA), hesperidin (HES), and their combinations (HES + CGA), on Lactuca sativa L. grown under normal- and mild-salinity conditions. To this aim, the phenolic profile, antioxidant properties, and enzyme inhibitory activity were determined. The untargeted metabolomics profiling revealed that lettuce treated with CGA under non-stressed conditions exhibited the highest total phenolic content (35.98 mg Eq./g). Lettuce samples grown under salt stress showed lower phenolic contents, except for lettuce treated with HES or HES + CGA, when comparing the same treatment between the two conditions. Furthermore, the antioxidant capacity was investigated through DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,20-azinobis-(3-ethylbenzothiazoline-6-sulfonate)), and FRAP (ferric reducing antioxidant power) assays, coupled with metal-chelating activity and phosphomolybdenum capacity. An exciting increase in radical scavenging capacity was observed in lettuce treated with exogenous phenolics, in both stress and non-stress conditions. The inhibitory activity of the samples was evaluated against target health-related enzymes, namely cholinesterases (acetylcholinesterase; AChE; butyryl cholinesterase; BChE), tyrosinase, α-amylase, and α-glucosidase. Lettuce treated with HES + CGA under non-stress conditions exhibited the strongest inhibition against AChE and BChE, while the same treatment under salinity conditions resulted in the highest inhibition capacity against α-amylase. Additionally, CGA under non-stress conditions exhibited the best inhibitory effect against tyrosinase. All the functional traits investigated were significantly modulated by exogenous phenolics, salinity, and their combination. In more detail, flavonoids, lignans, and stilbenes were the most affected phenolics, whereas glycosidase enzymes and tyrosinase activity were the most affected among enzyme assays. In conclusion, the exogenous application of phenolics to lettuce represents an effective and green strategy to effectively modulate the phenolic profile, antioxidant activity, and enzyme inhibitory effects in lettuce, deserving future application to produce functional plant-based foods in a sustainable way.

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Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects.

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Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects.

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