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Could small-diameter muscle afferents be responsible for the ergogenic effect of limb ischemic preconditioning?
2016; American Physiological Society; Volume: 122; Issue: 3 Linguagem: Inglês
10.1152/japplphysiol.00662.2016
ISSN8750-7587
AutoresRogério Santos de Oliveira Cruz, Kayo Leonardo Pereira, Felipe Domingos Lisbôa, Fabrízio Caputo,
Tópico(s)Anesthesia and Neurotoxicity Research
ResumoViewpointCould small-diameter muscle afferents be responsible for the ergogenic effect of limb ischemic preconditioning?Rogério Santos de Oliveira Cruz, Kayo Leonardo Pereira, Felipe Domingos Lisbôa, and Fabrizio CaputoRogério Santos de Oliveira CruzHuman Performance Research Group, College of Health and Sport Science, Santa Catarina State University, Brazil, Kayo Leonardo PereiraHuman Performance Research Group, College of Health and Sport Science, Santa Catarina State University, Brazil, Felipe Domingos LisbôaHuman Performance Research Group, College of Health and Sport Science, Santa Catarina State University, Brazil, and Fabrizio CaputoHuman Performance Research Group, College of Health and Sport Science, Santa Catarina State University, BrazilPublished Online:16 Mar 2017https://doi.org/10.1152/japplphysiol.00662.2016This is the final version - click for previous versionMoreSectionsPDF (92 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat originally developed with the aim of protecting cardiac muscle fibers from sustained ischemic insults, local or remote acute ischemic preconditioning (IP) consists of a potent endogenous mechanism that has been shown to protect various tissues and organs against ischemia-reperfusion injury (16, 28). Refined over the years, IP can now be conveniently elicited by multiple cycles of inflation and deflation of a standard blood pressure cuff on a limb to restrict the arterial blood inflow intermittently to an appendicular vascular bed of interest. As a result, a blood-borne factor, most likely produced downstream of the neural pathway, is released into the bloodstream, thus triggering a protective response against infarction, that is, reducing the subsequent damage caused by prolonged periods of imposed blood deprivation with subsequent reperfusion (20, 24). Somewhat surprisingly, limb IP before exercise has been shown to improve human motor performance in the most varied modalities, although not unanimously (e.g., 18), over a wide range of exercise durations (9, 10, 17, 22). However, the exact underlying pathways by which this noninvasive IP operates to enhance physical performance remain unknown.The mechanisms involved in the infarct-protective effect of remote IP are under intense investigation, and, to date, humoral and neuronal communications have been implicated (16, 20). According to a recent report from the 8th Biennial Hatter Cardiovascular Institute Workshop (20), although the actual identity of circulating humoral factors remains unknown, calcitonin gene-related peptide, hypoxia-inducible factor-1α, opioid peptides, and endogenous cannabinoids are included as candidates, recruiting intracellular signaling pathways from the remote organ or tissue, but a number of novel candidates continue to emerge. Furthermore, the current paradigm has proposed that, in response to the remote IP stimulus, endogenous autacoids, such adenosine and bradykinin, are produced in the remote organ or tissue, resulting in the nitric oxide-dependent stimulation of local afferent sensory nerves. Specifically, there is evidence suggesting thinly myelinated (Aδ, group III) and unmyelinated (C, group IV) afferent fibers are the essential first leg of neurotransmission (6, 7, 12, 21, 27, 31). It was reported that direct or indirect activation of the transient receptor potential vanilloid 1 (TRPV1) channels on these fibers by remote IP, capsaicin, or nociceptive stimuli may protect against ischemia-reperfusion injury (20, 27, 32). This protection has been at least partly attributed to the release of substance P and calcitonin gene-related peptide upon activation of TRPV1 (32). However, although these potential protective mediators could have a role in the complex chain of events driving the ergogenic effect of limb IP, actual experimental evidence is limited and constrained to physiological responses to exercise.Recently, Cruz et al. (9) showed that IP of the lower limbs increased the time until volitional exhaustion during a severe-intensity constant-load cycling exercise, which was closely related to a significantly higher slow-component of pulmonary V̇o2 onset-kinetics (and to a 3% gain in peak V̇o2). These changes were accompanied by an attenuation in the rate of increase in the ratings of perceived exertion (RPE) and a progressive increase in the myoelectrical activity of the vastus lateralis muscle throughout exercise. In a subsequent study, the 60-s cycling performance was improved after IP, owing to a less conservative pacing strategy (10). However, instead of improvements in aerobic energy metabolism, the benefit was followed by increases in the accumulated O2 deficit, the amplitude of blood lactate kinetics, the total amount of O2 consumed during recovery, and the overall electromyographic (EMG) amplitude. In addition, the ratio between EMG and power output was higher during the final third of performance after IP, which, combined with the metabolic responses, suggested a more severe degree of peripheral fatigue at the end of the performance. Taken together, the findings of Cruz et al. (9, 10) raised the following research questions. 1) Could lower discharges from the metabo-nociceptive subtype of sensory muscle afferents result in an overshoot in the central motor drive after IP? 2) If so, could this enhanced neural excitation of the exercising muscles be enabling the utilization of a higher fraction of the skeletal muscle recruitment “functional reserve” (5, 9, 10)? In our opinion, this is currently the best explanation for these findings (Fig. 1), because almost all of the aforementioned responses are obtained by blocking the pool of group III and IV fibers innervating the muscles with lumbar intrathecal fentanyl. It must be, however, recognized that the V̇o2 response to the subsequent exercise after fentanyl administration can be notably depressed (3). This particular discrepancy could be because the drug also blocks a subpopulation of muscle afferents fulfilling nonnociceptive functions (i.e., those ensuring adequate circulatory and ventilatory responses to exercise), which compromises muscle O2 delivery and consequently exercise tolerance (3, 5, 29). These so-called metabo- or ergoreceptors are most unlikely to be affected by limb IP (18); thus they are expected to discharge normally during the subsequent exercise. On the other hand, if muscle nociceptors play a major role in the ergogenic effects of IP, for a given performance to be successfully improved, the fraction of the muscular functional reserve usually inhibited by these neurons and made available through the IP procedure must be able to increase the total rate of energy release in a proportional manner. This would rely not only on the number of additional motor units recruited but also on their metabolic features in the context of exercise duration, whereas both may vary depending on a combination of participant and exercise characteristics (e.g., sex, training status, fiber type composition, exercised muscle group, and so forth). In addition to the different methods for implementing IP (e.g., a different time lag between IP and the start of exercise; 17), interactions among these factors could be partially accounting for the variability in between-study IP responsiveness.Fig. 1.Hypothetical sequence of events that could be driving the ergogenic effect of ischemic preconditioning (IP) on exercise performance. After limb IP, lower inhibitory inputs from muscle nociceptors to various sites within the central nervous system (CNS) could be enhancing the neural output to the active muscles, resulting in the recruitment of additional Type II muscle fibers. Note that this potential mechanism (thick boxes and black arrows) would be able to account directly or indirectly for all of the results reported by Cruz et al. (9, 10) (thin boxes and white arrows). Plus and minus signs denote positive or negative responses.Download figureDownload PowerPointOn the basis of the above considerations, an actual link between the protective and ergogenic mechanisms of IP now becomes plausible. Long-lasting desensitization/defunctionalization of the metabo-nociceptive subtype of afferent neurons after continuous stimulation of TRPV1 channels by limb IP is quite possible (8, 23, 26, 30, 32) and could “boost” the central motor drive/output at the spinal or supraspinal levels of motor control (5, 29, 30). In a recent investigation (8), intramuscular infusion of hypertonic saline, eliciting similar subjective pain ratings as limb IP (14), was shown to reduce short- and long-latency afferent inhibition. Unfortunately, in this study subjects were monitored only during the first 15 min after the resolution of acute pain. Likely due to the competitive interactions between afferent feedback and other inhibitory networks, the lower afferent discharges could only contribute to the partial restoration of normal (baseline) motor output. Thus the possible overshoot in motor output after an extended timeframe could not be seen. Nevertheless, the important point is that, not only do TRPV1 receptors respond to noxious hypertonic stimuli (2) but they have also been suggested as transduction molecules in the nociceptive detection of tissue ischemia (19). The TRPV1 channels can be sensitized/activated by arachidonic acid metabolites (e.g., prostaglandins and endocannabinoids) and bradykinin, which have been discussed in the context of IP and ischemia-reperfusion injury. In addition, although there is evidence suggesting that TRPV1 receptors contribute to the activation of the pressor responses during skeletal muscle contraction (see, e.g., 25), in some studies they were found neither to be contained in the metaboreceptors (11) nor to play a role in the exercise pressor reflex (13). Alternatively, or concomitantly, activation of opioid receptors by circulating endogenous opioid peptide(s) may participate, because it has been associated with the early phase of protection of either local acute or remote IP in several tissues, skeletal muscles included (1). Interestingly, these receptors are also present in the terminal endings of group III and IV muscle afferents (15). Therefore, excitation of opioid receptors might be decreasing the excitability of nociceptive peripheral nerve terminals, also resulting in lower spontaneous discharges to the central nervous system and thus reducing the inhibitory influences they exert on central motor efferent command (4). Irrespective of whether any of these speculative mechanisms play an actual role on the ergogenic effects of IP, they certainly strengthen the feasibility of these research questions, which need to be closely examined.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSR.S.d.O.C. drafted manuscript; R.S.d.O.C., K.L.P., F.D.L., and F.C. edited and revised manuscript; R.S.d.O.C., K.L.P., F.D.L., and F.C. approved final version of manuscript.ACKNOWLEDGMENTSThe authors thank Dr. Marc Kaufman (Heart and Vascular Institute, Penn State College of Medicine, Pennsylvania) for kind and thoughtful considerations in this manuscript.REFERENCES1. 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