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Mechanisms of prolonged low-frequency force depression: in vivo studies get us closer to the truth

2019; American Physiological Society; Volume: 316; Issue: 5 Linguagem: Inglês

10.1152/ajpregu.00063.2019

1522-1490

Thomas Chaillou, Arthur J. Cheng,

Sports Performance and Training

Editorial FocusMechanisms of prolonged low-frequency force depression: in vivo studies get us closer to the truthThomas Chaillou and Arthur J. ChengThomas ChaillouSchool of Health Sciences, Örebro University, Örebro, Sweden and Arthur J. ChengSchool of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, CanadaPublished Online:25 Apr 2019https://doi.org/10.1152/ajpregu.00063.2019This is the final version - click for previous versionMoreSectionsPDF (50 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Most everyday activities require low to moderate forces, which are generated by submaximal contractions. Fatigue-inducing exercise results in long-lasting depression in submaximal force postexercise called prolonged low-frequency force depression (PLFFD) (1). This state of PLFFD, which can persist for up to days after fatigue induction, is usually explained at the muscle fiber level by a decreased sarcoplasmic reticulum (SR) Ca2+ release and/or reduced myofibrillar Ca2+ sensitivity (2, 3). Notably, since submaximal contractions occur on the steep part of the force-cytosolic free Ca2+ concentration ([Ca2+]i) relationship, even minor changes in myofibrillar Ca2+ sensitivity or SR Ca2+ release can have a substantial impact on submaximal force production (4).Recent evidence implicates reactive oxygen species (ROS) generation for the decreased SR Ca2+ release and/or reduced myofibrillar Ca2+ sensitivity that underlies PLFFD. These ROS are produced during repeated intense muscle contractions and can lead to long-lasting oxidative modifications of muscle proteins (2, 3). The potential effect of antioxidant treatment on muscle function during recovery of PLFFD has already been previously investigated in in vitro studies using isolated intact fibers (3, 5). However, potential progress in our understanding of mechanisms underlying PLFFD can be made by studying PLFFD induced under more physiologically relevant conditions that take into consideration the normal intracellular environment typically surrounding muscle fibers. Indeed, in the current issue of American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Watanabe and colleagues (9) used an in vivo model to gain further insight into the role played by antioxidants on PLFFD in anesthetized male rats with intact blood supply to the fatigued muscles. In this study, rats were randomly divided into a control group and a group receiving an intraperitoneal injection of Eukarion-134 (EUK-134), a membrane-permeable mimetic of superoxide dismutase and catalase that can scavenge the major ROS superoxide and hydrogen peroxide, respectively. EUK-134 has recently been shown to be effective in counteracting intramuscular oxidative stress in rodent models of chronic diseases, such as pulmonary hypertension (6) and rheumatoid arthritis (10). Intact gastrocnemius muscles were electrically stimulated via the nerve to induce fatigue, while the muscles from the contralateral limbs remained unfatigued. Muscle isometric force was first evaluated at various stimulation frequencies, followed by a fatiguing protocol consisting of repeated contractions at 70 Hz every 3s until the force was reduced to ~50% of the initial force. Thirty minutes after the fatiguing contractions, the isometric force was reevaluated before the superficial regions of the stimulated and control gastrocnemius muscles were dissected to perform biochemical and skinned fiber analyses.Electrical stimulation-induced decreases in 20:100 Hz ratio in intact lower hindlimb muscles and 1:50 Hz force ratio in skinned gastrocnemius single fibers confirmed the presence of PLFFD induced in vivo. Watanabe et al. further revealed in control untreated rats that PLFFD induced in vivo was due to decreased SR Ca2+ release. Surprisingly, increased myofibrillar Ca2+ sensitivity was observed after fatiguing stimulation in this group, but this was not sufficient to counteract the suppression of submaximal force (i.e., PLFFD). This latter result was different from previous in vitro studies, which have largely shown decreased as opposed to increased myofibrillar Ca2+ sensitivity in intact muscle fibers after fatiguing stimulation (2, 3). Altogether, these findings from in vivo experiments add further confirmation of previous findings from in vitro experiments that PLFFD is primarily caused by decreased SR Ca2+ release (2, 3).Regarding the effects of antioxidant EUK-134 on PLFFD, Watanabe and colleagues found that EUK-134 had no effect on the fatigue-induced decrease in submaximal force in whole muscles, and EUK-134 did not affect the electrical stimulation-induced decrease in 1:50 Hz force ratio in skinned fibers (9). Their findings indicate that antioxidant treatment does not reverse PLFFD in vivo, although EUK-134 was able to partially offset the fatigue-induced decrease in SR Ca2+ release (compared with stimulated fibers from control rats, based on Fig. 4B in their paper) but this was counteracted by its negative effect on myofibrillar Ca2+ sensitivity (compared with stimulated fibers from control rats). On the other hand, a recent study showed that SS31 antioxidant treatment of mouse intact single fibers improved submaximal force after the fatiguing contractions compared with the untreated fibers (5). This result was explained by a positive effect of SS31 on myofibrillar Ca2+ sensitivity but not on SR Ca2+ release. These experiments were performed under physiological low O2 pressure (i.e., extracellular Po2 of ~5 Torr vs. intracellular Po2 is typically ~30 Torr in physiological normoxia at rest), indicating that conditions of low muscle O2 availability such as those observed during exercise at high altitude may alter the cellular site of action of the antioxidant on PLFFD. The results of Watanabe et al. (9) and Gandra et al. (5) highlight a complicated interplay between SR Ca2+ release and myofibrillar Ca2+ sensitivity, both important regulators of submaximal force generation but which are temporally and spatially sensitive to local redox alterations, and seem dependent on O2 availability. However, it is noteworthy that the positive effect of the antioxidant EUK-134 on SR Ca2+ release and its negative effect on myofibrillar Ca2+ sensitivity after fatiguing stimulations in vivo are in line with previous results from intact single fibers under supraphysiological extracellular Po2 (≥150 Torr) treated with the antioxidant SS31 (3) and intact single fibers from mice overexpressing mitochondrial superoxide dismutase 2 (2).So if ROS are implicated in PLFFD but antioxidants cannot mitigate these ROS-induced effects under normoxic conditions in vivo, what potential conclusions can we draw? Watanabe et al. show supporting data that increased ROS generation is largely beneficial for increasing myofibrillar Ca2+ sensitivity through ROS-induced S-glutathionylation of fast troponin I, the dominating mechanism for ROS-induced alterations in myofibrillar Ca2+ sensitivity (9). These data are consistent with recent evidence supporting beneficial as opposed to negative effects of ROS on skeletal muscle function (8). Specifically, antioxidants can have acute positive effects on SR Ca2+ release as observed by Watanabe et al. and others (2, 3) but deleterious long-term effects on ROS-modulated signaling pathways that could impair chronic endurance training adaptations (7).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONST.C. and A.J.C. drafted manuscript; T.C. and A.J.C. edited and revised manuscript; T.C. and A.J.C. approved final version of manuscript.REFERENCES1. Allen DG, Lamb GD, Westerblad H. Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88: 287–332, 2008. doi:10.1152/physrev.00015.2007. Link | ISI | Google Scholar2. Bruton JD, Place N, Yamada T, Silva JP, Andrade FH, Dahlstedt AJ, Zhang SJ, Katz A, Larsson NG, Westerblad H. Reactive oxygen species and fatigue-induced prolonged low-frequency force depression in skeletal muscle fibres of rats, mice and SOD2 overexpressing mice. J Physiol 586: 175–184, 2008. doi:10.1113/jphysiol.2007.147470. Crossref | PubMed | ISI | Google Scholar3. Cheng AJ, Bruton JD, Lanner JT, Westerblad H. Antioxidant treatments do not improve force recovery after fatiguing stimulation of mouse skeletal muscle fibres. J Physiol 593: 457–472, 2015. doi:10.1113/jphysiol.2014.279398. Crossref | PubMed | ISI | Google Scholar4. Cheng AJ, Yamada T, Rassier DE, Andersson DC, Westerblad H, Lanner JT. Reactive oxygen/nitrogen species and contractile function in skeletal muscle during fatigue and recovery. J Physiol 594: 5149–5160, 2016. doi:10.1113/JP270650. Crossref | PubMed | ISI | Google Scholar5. Gandra PG, Shiah AA, Nogueira L, Hogan MC. A mitochondrial-targeted antioxidant improves myofilament Ca2+ sensitivity during prolonged low frequency force depression at low PO2. J Physiol 596: 1079–1089, 2018. doi:10.1113/JP275470. Crossref | PubMed | ISI | Google Scholar6. Himori K, Abe M, Tatebayashi D, Lee J, Westerblad H, Lanner JT, Yamada T. Superoxide dismutase/catalase mimetic EUK-134 prevents diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension. PLoS One 12: e0169146, 2017. doi:10.1371/journal.pone.0169146. Crossref | PubMed | ISI | Google Scholar7. Merry TL, Ristow M. Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training? J Physiol 594: 5135–5147, 2016. doi:10.1113/JP270654. Crossref | PubMed | ISI | Google Scholar8. Merry TL, Ristow M. Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) mediates exercise-induced mitochondrial biogenesis and the anti-oxidant response in mice. J Physiol 594: 5195–5207, 2016. doi:10.1113/JP271957. Crossref | PubMed | ISI | Google Scholar9. Watanabe D, Aibara C, Wada M. Treatment with EUK-134 improves sarcoplasmic reticulum Ca2+ release but not myofibrillar Ca2+ sensitivity after fatiguing contraction of rat fast-twitch muscle. Am J Physiol Regul Integr Comp Physiol ajpregu.00387.2018, 2019. doi:10.1152/ajpregu.00387.2018. Link | ISI | Google Scholar10. Yamada T, Abe M, Lee J, Tatebayashi D, Himori K, Kanzaki K, Wada M, Bruton JD, Westerblad H, Lanner JT. Muscle dysfunction associated with adjuvant-induced arthritis is prevented by antioxidant treatment. Skelet Muscle 5: 20, 2015. doi:10.1186/s13395-015-0045-7. Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: A. Cheng, School of Kinesiology and Health Science, Faculty of Health, 341 Norman Bethune College, 4700 Keele St., Toronto, Ontario M3J 1P3, Canada. Download PDF Back to Top Next FiguresReferencesRelatedInformation Related ArticlesTreatment with EUK-134 improves sarcoplasmic reticulum Ca2+ release but not myofibrillar Ca2+ sensitivity after fatiguing contraction of rat fast-twitch muscle 25 Apr 2019American Journal of Physiology-Regulatory, Integrative and Comparative PhysiologyCited ByElectromyography and Dynamometry for Investigating the Neuromuscular Control of the Foot and AnkleHow to evaluate skeletal muscle function: suggestion from studies on skeletal muscle fatigueFolia Pharmacologica Japonica, Vol. 157, No. 1Maximal results with minimal stimuli: the fewest high-frequency pulses needed to measure or model prolonged low-frequency force depression in the dorsiflexorsLuca Ruggiero, Christina D. Bruce, Hannah B. Streight, and Chris J. McNeil11 August 2021 | Journal of Applied Physiology, Vol. 131, No. 2Carbohydrates do not accelerate force recovery after glycogen‐depleting followed by high‐intensity exercise in humans6 April 2020 | Scandinavian Journal of Medicine & Science in Sports, Vol. 30, No. 6 More from this issue > Volume 316Issue 5May 2019Pages R502-R503 Copyright & PermissionsCopyright © 2019 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00063.2019PubMed30892917History Received 28 February 2019 Accepted 1 March 2019 Published online 25 April 2019 Published in print 1 May 2019 Metrics