Fatigue in working muscles

INVITED EDITORIALFatigue in working musclesDavid G. AllenDavid G. AllenPublished Online:01 Feb 2009https://doi.org/10.1152/japplphysiol.91599.2008This is the final version - click for previous versionMoreSectionsPDF (121 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations muscle performance declines with intense use as every physically active person recognizes. The mechanisms involved have been widely studied (2) and vary with the intensity, duration, and mechanics (shortening, isometric, stretching) of the contractions involved. While performance and fatigue obviously have contributions from the central nervous system, a common experimental approach avoids these complications by studying isolated muscles. A typical approach uses an isolated muscle, perfused with physiological saline at room temperature, and stimulates isometric tetani repeatedly until the force is substantially reduced, e.g., Fig. 1.Of course such methods have many limitations, some of which are well recognized. For instance, only relatively recently was it realized that the "lactic acid theory of fatigue" was very important at low temperatures (frogs in winter and mammalian muscles at room temperature) but of minor importance in mammalian muscles close to 37°C (8, 10). Another well-recognized problem is that isolated whole muscles without circulation will tend to have an anoxic core and also accumulate extracellular K+, so that the mechanisms of fatigue in such a preparation are modified by these issues. To overcome the core accumulation problem, smaller preparations, such as single fibers, are often used, but these present another series of possible artifacts; for instance, they will not show the accumulation of extracellular K+ that occurs in a blood-perfused preparation.Studies on isolated single fibers, in which metabolites and ionic levels can be measured, coupled with studies of skinned fibers, which allow the effects of metabolites on contractile proteins and Ca2+ release from the sarcoplasmic reticulum (SR), have provided the following view of the mechanisms of fatigue (Fig. 1). Note that these mechanisms apply to isolated single muscle cells at room temperature, stimulated to give maximal, repeated isometric tetani. Under these circumstances, force falls in three phases. Phase 1 involves a reduction of force to 80–90% control over ∼1 min and is generally thought to be caused by the inhibitory effect of inorganic phosphate (Pi) on the transition of the cross bridge to its high-force state (7). In phase 2, force is relatively constant and production of ATP from aerobic and anaerobic breakdown of glycogen matches the rate of ATP consumption. In phase 3, force starts to decline again caused principally by the reduction in SR Ca2+ release (reduced Ca2+ transients) coupled to reduced sensitivity of the contractile proteins to Ca2+. The mechanism of the decline in Ca2+ release is still debated (1).The above conditions are obviously artificial, and many studies of fatigue have been performed in intact animals and humans to minimize these problems. Equally obviously the range of investigations available in an intact animal is more limited and it is consequently more difficult to pin down mechanisms. Thus another approach is to progressively make the isolated muscles "more physiological" by raising the temperature, using shortening contractions instead of isometric, perfusing through the circulation with blood, etc. In this context, the study in the Journal of Applied Physiology by Roots et al. (9) utilized isolated, small bundles of fast fibers from rat muscle and looked at their performance at a range of temperatures (10–30°C) and when shortening contractions were used instead of isometric contractions. One striking result was that the rate of fatigue was slower at 30°C than at 10°C. This is surprising because most earlier studies have reported faster fatigue at near-physiological temperatures (4). This is often explained by the fact that ATPases will be faster at higher temperatures, so that ATP consumption and Pi production will accelerate. Of course ATP resynthesis will also accelerate so this argument alone is incomplete. Roots et al. (9) make the point that the sensitivity of force production to Pi also falls with increasing temperature (5) and propose this as the explanation for their effect. A full quantitative analysis will require Pi measurements during fatigue at different temperatures in addition to the sensitivity changes, and this analysis remains to be done. Of course many other issues may contribute to the temperature dependence of fatigue, for instance the increased reactive oxygen species production that occurs at higher temperatures (3).A second interesting conclusion from the study by Roots et al. (9) was the finding that muscles fatigued more rapidly when contractions involving shortening were compared to isometric. A plausible explanation is that shortening contractions consume ATP at a higher rate than isometric contractions (6), so that Pi accumulation is greater and the depressive effect of Pi on force production is also increased. While plausible, this argument has not been quantified and other mechanisms may well contribute to the effect.Studies of fatigue have reached the point where the mechanisms are moderately well defined in some simplified preparations. An important challenge is to extend these studies to more physiological conditions, and the study by Roots et al. (9) is a valuable step in this direction. A greater challenge is to define the mechanisms of fatigue in human diseases, e.g., heart failure, serious infections, etc.; identification of these mechanisms is necessary before attempts can be made to ameliorate such conditions. Fig. 1.Schematic of fatigue in an isolated single fiber at room temperature stimulated with repeated, brief isometric tetani. The 3 phases of force decline are identified and relevant intracellular changes noted.Download figureDownload PowerPointREFERENCES1 Allen DG, Lamb GD, Westerblad H. Impaired calcium release during fatigue. J Appl Physiol 104: 296–305, 2008.Link | ISI | Google Scholar2 Allen DG, Lamb GD, Westerblad H. Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88: 287–332, 2008.Link | ISI | Google Scholar3 Arbogast S, Reid MB. Oxidant activity in skeletal muscle fibers is influenced by temperature, CO2 level, and muscle-derived nitric oxide. Am J Physiol Regul Integr Comp Physiol 287: R698–R705, 2004.Link | ISI | Google Scholar4 de Ruiter CJ, de Haan A. Temperature effect on the force/velocity relationship of the fresh and fatigued human adductor pollicis muscle. Pflügers Arch 440: 163–170, 2000.Crossref | PubMed | ISI | Google Scholar5 Debold EP, Dave H, Fitts RH. Fiber type and temperature dependence of inorganic phosphate: implications for fatigue. Am J Physiol Cell Physiol 287: C673–C681, 2004.Link | ISI | Google Scholar6 Fenn WO. The relation between the work performed and the energy liberated in muscular contraction. J Physiol 58: 373–395, 1924.Crossref | PubMed | Google Scholar7 Millar NC, Homsher E. The effect of phosphate and calcium on force generation in glycerinated rabbit skeletal muscle fibers; a steady-state and transient kinetic study. J Biol Chem 265: 20234–20240, 1990.Crossref | PubMed | ISI | Google Scholar8 Pate E, Bhimani M, Franks-Skiba K, Cooke R. Reduced effect of pH on skinned rabbit psoas muscle mechanics at high temperatures: implications for fatigue. J Physiol 486: 689–694, 1995.Crossref | PubMed | ISI | Google Scholar9 Roots H, Ball G, Talbot-Ponsonby J, King M, McBeath K, Ranatunga KW. Muscle fatigue examined at different temperatures in experiments on intact mammalian (rat) muscle fibers. J Appl Physiol (December 4, 2008). doi:10.1152/japplphysiol.90883.2008.Link | Google Scholar10 Westerblad H, Allen DG, Lannergren J. Muscle fatigue: lactic acid or inorganic phosphate the major cause? News Physiol Sci 17, 17–21, 2002.Abstract | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: D. G. Allen, School of Medical Sciences and Bosch Institute, Univ. of sydney, Sydney, NSW 2006, Australia (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByEvidence-based and adverse-effects analyses of cupping therapy in musculoskeletal and sports rehabilitation: A systematic and evidence-based reviewJournal of Back and Musculoskeletal Rehabilitation, Vol. 36, No. 1Molecular Characterization of Tropomyosin and Its Potential Involvement in Muscle Contraction in Pacific Abalone20 December 2022 | Genes, Vol. 14, No. 1Heat-induced endoplasmic reticulum stress in soleus and gastrocnemius muscles and differential response to UPR pathway in rats18 November 2020 | Cell Stress and Chaperones, Vol. 26, No. 2Exploring the role of fatigue-related metabolite activity during high-intensity exercise using a simplified whole-body mathematical modelInformatics in Medicine Unlocked, Vol. 19Neuromuscular manifestations of work-related myalgia in women specific to extensor carpi radialis brevisCanadian Journal of Physiology and Pharmacology, Vol. 95, No. 4Muscle metabolic and neuromuscular determinants of fatigue during cycling in different exercise intensity domainsMatthew I. 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La récupération chez la femme sportive More from this issue > Volume 106Issue 2February 2009Pages 358-359 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.91599.2008PubMed19095748History Published online 1 February 2009 Published in print 1 February 2009 Metrics