Resting membrane potential and intracellular [Na+] at rest, during fatigue and during recovery in rat soleus muscle fibres in situ.

Large trans-sarcolemmal ionic shifts occur with fatiguing exercise or stimulation of isolated muscles. However, it is unknown how resting membrane potential (EM) and intracellular sodium concentration ([Na+]i) change with repeated contractions in living mammals. We investigated (i) whether [Na+]i (peak, kinetics) can reveal changes of Na+-K+ pump activity during brief or fatiguing stimulation and (ii) how resting EM and [Na+]i change during fatigue and recovery of rat soleus muscle in situ. Muscles of anaesthetised rats were stimulated with brief (10 s) or repeated tetani (60 Hz for 200 ms, every 2 s, for 30 s or 300 s) with isometric force measured. Double-barrelled ion-sensitive microelectrodes were used to quantify resting EM and [Na+]i. Post-stimulation data were fitted using polynomials and back-extrapolated to time zero recovery. Mean pre-stimulation resting EM (layer 2-7 fibres) was -71 mV (surface fibres were more depolarised), and [Na+]i was 14 mM. With deeper fibres, 10 s stimulation (2-150 Hz) increased [Na+]i to 38-46 mM whilst simultaneously causing hyperpolarisations (7.3 mV for 2-90 Hz). Fatiguing stimulation for 30 s or 300 s led to end-stimulation resting EM of -61 to -53 mV, which recovered rapidly (T1/2, 8-22 s). Mean end-stimulation [Na+]i increased to 86-101 mM with both fatigue protocols and the [Na+]i recovery time-course (T1/2, 21-35 s) showed no difference between protocols. These combined findings suggest that brief stimulation hyperpolarises the resting EM, likely via maximum Na+-induced stimulation of the Na+-K+ pump. Repeated tetani caused massive depolarisation and elevations of [Na+]i that together lower force, although they likely interact with other factors to cause fatigue. [Na+]i recovery kinetics provided no evidence of impaired Na+-K+ pump activity with fatigue. KEY POINTS: It is uncertain how resting membrane potential, intracellular sodium concentration ([Na+]i), and sodium-potassium (Na+-K+) pump activity change during repeated muscle contractions in living mammals. For rat soleus muscle fibres in situ, brief tetanic stimulation for 10 s led to raised [Na+]i, anticipated to evoke maximal Na+-induced stimulation of the Na+-K+ pump causing an immediate hyperpolarisation of the sarcolemma. More prolonged stimulation with repeated tetanic contractions causes massive elevations of [Na+]i, which together with large depolarisations (via K+ disturbances) likely reduce force production. These effects occurred without impairment of Na+-K+ pump function. Together these findings suggest that rapid activation of the Na+-K+ pump occurs with brief stimulation to maintain excitability, whereas more prolonged stimulation causes rundown of the trans-sarcolemmal K+ gradient (hence depolarisation) and Na+ gradient, which in combination can impair contraction to contribute to fatigue in living mammals.

The potassium-glycogen interaction on force and excitability in mouse skeletal muscle: implications for fatigue.

A reduced muscle glycogen content and potassium (K+ ) disturbances across muscle membranes occur concomitantly during repeated intense exercise and together may contribute to skeletal muscle fatigue. Therefore, we examined whether raised extracellular K+ concentration ([K+ ]o ) (4 to 11 mM) interacts with lowered glycogen to reduce force production. Isometric contractions were evoked in isolated mouse soleus muscles (37°C) using direct supramaximal field stimulation. (1) Glycogen declined markedly in non-fatigued muscle with >2 h exposure in glucose-free physiological saline compared with control solutions (11 mM glucose), i.e. to <45% control. (2) Severe glycogen depletion was associated with increased 5'-AMP-activated protein kinase activity, indicative of metabolic stress. (3) The decline of peak tetanic force at 11 mM [K+ ]o was exacerbated from 67% initial at normal glycogen to 22% initial at lowered glycogen. This was due to a higher percentage of inexcitable fibres (71% vs. 43%), yet without greater sarcolemmal depolarisation or smaller amplitude action potentials. (4) Returning glucose while at 11 mM [K+ ]o increased both glycogen and force. (5) Exposure to 4 mM [K+ ]o glucose-free solutions (15 min) did not increase fatiguability during repeated tetani; however, after recovery there was a greater force decline at 11 mM [K+ ]o at lower than normal glycogen. (6) An important exponential relationship was established between relative peak tetanic force at 11 mM [K+ ]o and muscle glycogen content. These findings provide direct evidence of a synergistic interaction between raised [K+ ]o and lowered muscle glycogen as the latter shifts the peak tetanic force-resting EM relationship towards more negative resting EM due to lowered sarcolemmal excitability, which hence may contribute to muscle fatigue. KEY POINTS: Diminished muscle glycogen levels and raised extracellular potassium concentrations ([K+ ]o ) occur simultaneously during intense exercise and together may contribute to muscle fatigue. Prolonged exposure of isolated non-fatigued soleus muscles of mice to glucose-free physiological saline solutions markedly lowered muscle glycogen levels, as does fatigue then recovery in glucose-free solutions. For both approaches, the subsequent decline of maximal force at 11 mM [K+ ]o , which mimics interstitial [K+ ] levels during intense exercise, was exacerbated at lowered compared with normal glycogen. This was mainly due to many more muscle fibres becoming inexcitable. We established an important relationship that provides evidence of a synergistic interaction between raised [K+ ]o and lowered glycogen content to reduce force production. This paper indicates that partially lowered muscle glycogen (and/or metabolic stress) together with elevated interstitial [K+ ] interactively lowers muscle force, and hence may diminish performance especially during repeated high-intensity exercise.

Plasma Acidosis and Peak Power after a Supramaximal Trial in Elite Sprint and Endurance Cyclists: Effect of Bicarbonate.

PURPOSE: This study aimed to determine whether (i) a plasma acidosis contributes to a reduction of mechanical performance and (ii) bicarbonate supplementation blunts plasma acidosis and arterial oxygen desaturation to resist fatigue during the end spurt of a supramaximal trial in elite sprint and endurance cyclists. METHODS: Elite/world-class cyclists ( n = 6 sprint, n = 6 endurance) completed two randomized, double-blind, crossover trials at 105%V̇O 2peak simulating 3 min of a 4-km individual pursuit, 90 min after ingestion of 0.3 g·kg -1 BM sodium bicarbonate (BIC) or placebo (PLA). Peak power output (PPO), optimal cadence and optimal peak torque, and fatigue were assessed using a 6-s "all-out sprint" before (PPO1) and after (PPO2) each trial. Plasma pH, bicarbonate, lactate - , K + , Na + , Ca 2+ , and arterial hemoglobin saturation (SpO 2 (%)), were measured. RESULTS: Sprint cyclists exhibited a higher PPO, optimal pedal torque, and anaerobic power reserve (APR) than endurance cyclists. The trial reduced PPO (PLA) more for sprint (to 47% initial) than endurance cyclists (to 61% initial). Optimal cadence fell from ~151 to 92 rpm and cyclists with higher APR exhibited a reduced optimal peak torque. Plasma pH fell from 7.35 to 7.13 and plasma [lactate - ] increased from 1.2 to 19.6 mM (PLA), yet neither correlated with PPO loss. Sprint cyclists displayed a lesser plasma acidosis but greater fatigue than endurance cyclists. BIC increased plasma [HCO 3- ] (+6.8 mM) and plasma pH after PPO1 (+0.09) and PPO2 (+0.07) yet failed to influence mechanical performance. SpO 2 fell from 99% to 96% but was unrelated to the plasma acidosis and unaltered with BIC. CONCLUSIONS: Plasma acidosis was not associated with the decline of PPO in a supramaximal trial with elite cyclists. BIC attenuated acid-base disturbances yet did not improve arterial oxygen desaturation or mechanical performance at the end-spurt stage.

The peak force-resting membrane potential relationships of mouse fast- and slow-twitch muscle.

We endeavored to understand the factors determining the peak force-resting membrane potential (EM) relationships of isolated slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles from mice (25°C), especially in relation to fatigue. Interrelationships between intracellular K+ activity ([Formula: see text]), extracellular K+ concentration ([K+]o), resting EM, action potentials, and force were studied. The large resting EM variation was mainly due to the variability of [Formula: see text]. Action potential overshoot-resting EM relationships determined at 4 and 8-10 mM [K+]o after short (<5 min) and prolonged (>50 min) depolarization periods revealed a constant overshoot from -90 to -70 mV providing a safety margin. Overshoot decline with depolarization beyond -70 mV was less after short than prolonged depolarization. Inexcitable fibers occurred only with prolonged depolarization. The overshoot decline during action potential trains (2 s) exceeded that during short depolarizations. Concomitant lower extracellular [Na+] and raised [K+]o depressed the overshoot in an additive manner and peak force in a synergistic manner. Raised [K+]o-induced force loss was exacerbated with transverse wire versus parallel plate stimulation in soleus, implicating action potential propagation failure in the surface membrane. Increasing stimulus pulse parameters restored tetanic force at 9-10 mM [K+]o in soleus but not EDL, indicative of action potential failure within trains. The peak tetanic force-resting EM relationships (determined with resting EM from deeper rather than surface fibers) were dynamic and showed pronounced force depression over -69 to -60 mV in both muscle types, implicating that such depolarization contributes to fatigue. The K+-Na+ interaction shifted this relationship toward less depolarized potentials, suggesting that the combined ionic effect is physiologically important during fatigue.

Regulation of muscle potassium: exercise performance, fatigue and health implications.

This review integrates from the single muscle fibre to exercising human the current understanding of the role of skeletal muscle for whole-body potassium (K+) regulation, and specifically the regulation of skeletal muscle [K+]. We describe the K+ transport proteins in skeletal muscle and how they contribute to, or modulate, K+ disturbances during exercise. Muscle and plasma K+ balance are markedly altered during and after high-intensity dynamic exercise (including sports), static contractions and ischaemia, which have implications for skeletal and cardiac muscle contractile performance. Moderate elevations of plasma and interstitial [K+] during exercise have beneficial effects on multiple physiological systems. Severe reductions of the trans-sarcolemmal K+ gradient likely contributes to muscle and whole-body fatigue, i.e. impaired exercise performance. Chronic or acute changes of arterial plasma [K+] (hyperkalaemia or hypokalaemia) have dangerous health implications for cardiac function. The current mechanisms to explain how raised extracellular [K+] impairs cardiac and skeletal muscle function are discussed, along with the latest cell physiology research explaining how calcium, ß-adrenergic agonists, insulin or glucose act as clinical treatments for hyperkalaemia to protect the heart and skeletal muscle in vivo. Finally, whether these agents can also modulate K+-induced muscle fatigue are evaluated.

Central activation, metabolites, and calcium handling during fatigue with repeated maximal isometric contractions in human muscle.

PURPOSE: To determine the roles of calcium (Ca2+) handling by sarcoplasmic reticulum (SR) and central activation impairment (i.e., central fatigue) during fatigue with repeated maximal voluntary isometric contractions (MVC) in human muscles. METHODS: Contractile performance was assessed during 3 min of repeated MVCs (7-s contraction, 3-s rest, n = 17). In ten participants, in vitro SR Ca2+-handling, metabolites, and fibre-type composition were quantified in biopsy samples from quadriceps muscle, along with plasma venous [K+]. In 11 participants, central fatigue was compared using tetanic stimulation superimposed on MVC in quadriceps and adductor pollicis muscles. RESULTS: The decline of peak MVC force with fatigue was similar for both muscles. Fatigue resistance correlated directly with % type I fibre area in quadriceps (r = 0.77, P = 0.009). The maximal rate of ryanodine-induced Ca2+-release and Ca2+-uptake fell by 31 ± 26 and 28 ± 13%, respectively. The tetanic force depression was correlated with the combined reduction of ATP and PCr, and increase of lactate (r = 0.77, P = 0.009). Plasma venous [K+] increased from 4.0 ± 0.3 to 5.4 ± 0.8 mM over 1-3-min exercise. Central fatigue occurred during the early contractions in the quadriceps in 7 out of 17 participants (central activation ratio fell from 0.98 ± 0.05 to 0.86 ± 0.11 at 1 min), but dwindled at exercise cessation. Central fatigue was seldom apparent in adductor pollicis. CONCLUSIONS: Fatigue with repeated MVC in human limb muscles mainly involves peripheral aspects which include impaired SR Ca2+-handling and we speculate that anaerobic metabolite changes are involved. A faster early force loss in quadriceps muscle with some participants is attributed to central fatigue.

Do Fast Bowlers Fatigue in Cricket? A Paradox Between Player Anecdotes and Quantitative Evidence.

The manifestations of fatigue during fast bowling in cricket were systematically evaluated using subjective reports by cricket experts and quantitative data published from scientific studies. Narratives by international players and team physiotherapists were sourced from the Internet using criteria for opinion-based evidence. Research articles were evaluated for high-level fast bowlers who delivered 5- to 12-over spells with at least 1 quantitative fatigue measure. Anecdotes indicate that a long-term loss of bowling speed, tiredness, mental fatigue, and soreness occur. Scientific research shows that ball-release speed, bowling accuracy, bowling action (technique), run-up speed, and leg-muscle power are generally well maintained during bowling simulations. However, bowlers displaying excessive shoulder counterrotation toward the end of a spell also show a fall in accuracy. A single notable study involving bowling on 2 successive days in the heat showed reduced ball-release speed (-4.4 km/h), run-up speed (-1.3 km/h), and accuracy. Moderate to high ratings of perceived exertion transpire with simulations and match play (6.5-7.5 Borg CR-10 scale). Changes of blood lactate, pH, glucose, and core temperature appear insufficient to impair muscle function, although several potential physiological fatigue factors have not been investigated. The limited empirical evidence for bowling-induced fatigue appears to oppose player viewpoints and indicates a paradox. However, this may not be the case since bowling simulations resemble the shorter formats of the game but not multiday (test match) cricket or the influence of an arduous season, and comments of tiredness, mental fatigue, and soreness signify phenomena different from what scientists measure as fatigue.

ß-Adrenergic modulation of skeletal muscle contraction: key role of excitation-contraction coupling.

Our aim is to describe the acute effects of catecholamines/ß-adrenergic agonists on contraction of non-fatigued skeletal muscle in animals and humans, and explain the mechanisms involved. Adrenaline/ß-agonists (0.1-30 µm) generally augment peak force across animal species (positive inotropic effect) and abbreviate relaxation of slow-twitch muscles (positive lusitropic effect). A peak force reduction also occurs in slow-twitch muscles in some conditions. ß2 -Adrenoceptor stimulation activates distinct cyclic AMP-dependent protein kinases to phosphorylate multiple target proteins. ß-Agonists modulate sarcolemmal processes (increased resting membrane potential and action potential amplitude) via enhanced Na(+) -K(+) pump and Na(+) -K(+) -2Cl(-) cotransporter function, but this does not increase force. Myofibrillar Ca(2+) sensitivity and maximum Ca(2+) -activated force are unchanged. All force potentiation involves amplified myoplasmic Ca(2+) transients consequent to increased Ca(2+) release from sarcoplasmic reticulum (SR). This unequivocally requires phosphorylation of SR Ca(2+) release channels/ryanodine receptors (RyR1) which sensitize the Ca(2+) -induced Ca(2+) release mechanism. Enhanced trans-sarcolemmal Ca(2+) influx through phosphorylated voltage-activated Ca(2+) channels contributes to force potentiation in diaphragm and amphibian muscle, but not mammalian limb muscle. Phosphorylation of phospholamban increases SR Ca(2+) pump activity in slow-twitch fibres but does not augment force; this process accelerates relaxation and may depress force. Greater Ca(2+) loading of SR may assist force potentiation in fast-twitch muscle. Some human studies show no significant force potentiation which appears to be related to the ß-agonist concentration used. Indeed high-dose ß-agonists (∼0.1 µm) enhance SR Ca(2+) -release rates, maximum voluntary contraction strength and peak Wingate power in trained humans. The combined findings can explain how adrenaline/ß-agonists influence muscle performance during exercise/stress in humans.

Extracellular Ca2+-induced force restoration in K+-depressed skeletal muscle of the mouse involves an elevation of [K+]i: implications for fatigue.

We examined whether a Ca(2+)-K(+) interaction was a potential mechanism operating during fatigue with repeated tetani in isolated mouse muscles. Raising the extracellular Ca(2+) concentration ([Ca(2+)]o) from 1.3 to 10 mM in K(+)-depressed slow-twitch soleus and/or fast-twitch extensor digitorum longus muscles caused the following: 1) increase of intracellular K(+) activity by 20-60 mM (raised intracellular K(+) content, unchanged intracellular fluid volume), so that the K(+)-equilibrium potential increased by ∼10 mV and resting membrane potential repolarized by 5-10 mV; 2) large restoration of action potential amplitude (16-54 mV); 3) considerable recovery of excitable fibers (∼50% total); and 4) restoration of peak force with the peak tetanic force-extracellular K(+) concentration ([K(+)]o) relationship shifting rightward toward higher [K(+)]o. Double-sigmoid curve-fitting to fatigue profiles (125 Hz for 500 ms, every second for 100 s) showed that prior exposure to raised [K(+)]o (7 mM) increased, whereas lowered [K(+)]o (2 mM) decreased, the rate and extent of force loss during the late phase of fatigue (second sigmoid) in soleus, hence implying a K(+) dependence for late fatigue. Prior exposure to 10 mM [Ca(2+)]o slowed late fatigue in both muscle types, but was without effect on the extent of fatigue. These combined findings support our notion that a Ca(2+)-K(+) interaction is plausible during severe fatigue in both muscle types. We speculate that a diminished transsarcolemmal K(+) gradient and lowered [Ca(2+)]o contribute to late fatigue through reduced action potential amplitude and excitability. The raised [Ca(2+)]o-induced slowing of fatigue is likely to be mediated by a higher intracellular K(+) activity, which prolongs the time before stimulation-induced K(+) efflux depolarizes the sarcolemma sufficiently to interfere with action potentials.

Changes of whole-body power, muscle function, and jump performance with prolonged cycling to exhaustion.

PURPOSE: To quantify how whole-body power, muscle-function, and jump-performance measures change during prolonged cycling and recovery and determine whether there are relationships between the different fatigue measures. METHODS: Ten competitive or recreationally active male cyclists underwent repeated 20-min stages of prolonged cycling at 70% VO2peak until exhaustion. Whole-body peak power output (PPO) was assessed using an all-out 30-s sprint 17 min into each cycle stage. Ratings of perceived exertion (RPE) were recorded throughout. Isometric and isokinetic muscle-function tests were made between cycle stages, over ~6 min, and during 30-min recovery. Drop-jump measures were tested at exhaustion and during recovery. RESULTS: PPO initially increased or was maintained in some subjects but fell to 81% of maximum at exhaustion. RPE was near maximal (18.7) at exhaustion, with the time to exhaustion related to the rate of rise of RPE. PPO first started to decline only when RPE exceeded 16 (ie, hard). Peak isometric and concentric isokinetic torque (180°/s) for the quadriceps fell to 86% and 83% of pretest at exhaustion, respectively. In contrast, the peak concentric isokinetic torque (180°/s) of the hamstrings increased by 10% before declining to 93% of maximum. Jump height fell to 92% of pretest at exhaustion and was correlated with the decline in PPO (r = .79). Muscle-function and jump-performance measures did not recover over the 30-min postexercise rest period. CONCLUSIONS: At exhaustion, whole-body power, muscle-function, and jump-performance measures had all fallen by 7-19%. PPO and drop-jump decrements were linearly correlated and are appropriate measures of maximal performance.

Myosin filament polymerization and depolymerization in a model of partial length adaptation in airway smooth muscle.

Length adaptation in airway smooth muscle (ASM) is attributed to reorganization of the cytoskeleton, and in particular the contractile elements. However, a constantly changing lung volume with tidal breathing (hence changing ASM length) is likely to restrict full adaptation of ASM for force generation. There is likely to be continuous length adaptation of ASM between states of incomplete or partial length adaption. We propose a new model that assimilates findings on myosin filament polymerization/depolymerization, partial length adaptation, isometric force, and shortening velocity to describe this continuous length adaptation process. In this model, the ASM adapts to an optimal force-generating capacity in a repeating cycle of events. Initially the myosin filament, shortened by prior length changes, associates with two longer actin filaments. The actin filaments are located adjacent to the myosin filaments, such that all myosin heads overlap with actin to permit maximal cross-bridge cycling. Since in this model the actin filaments are usually longer than myosin filaments, the excess length of the actin filament is located randomly with respect to the myosin filament. Once activated, the myosin filament elongates by polymerization along the actin filaments, with the growth limited by the overlap of the actin filaments. During relaxation, the myosin filaments dissociate from the actin filaments, and then the cycle repeats. This process causes a gradual adaptation of force and instantaneous adaptation of shortening velocity. Good agreement is found between model simulations and the experimental data depicting the relationship between force development, myosin filament density, or shortening velocity and length.

Interactive processes link the multiple symptoms of fatigue in sport competition.

Muscle physiologists often describe fatigue simply as a decline of muscle force and infer this causes an athlete to slow down. In contrast, exercise scientists describe fatigue during sport competition more holistically as an exercise-induced impairment of performance. The aim of this review is to reconcile the different views by evaluating the many performance symptoms/measures and mechanisms of fatigue. We describe how fatigue is assessed with muscle, exercise or competition performance measures. Muscle performance (single muscle test measures) declines due to peripheral fatigue (reduced muscle cell force) and/or central fatigue (reduced motor drive from the CNS). Peak muscle force seldom falls by >30% during sport but is often exacerbated during electrical stimulation and laboratory exercise tasks. Exercise performance (whole-body exercise test measures) reveals impaired physical/technical abilities and subjective fatigue sensations. Exercise intensity is initially sustained by recruitment of new motor units and help from synergistic muscles before it declines. Technique/motor skill execution deviates as exercise proceeds to maintain outcomes before they deteriorate, e.g. reduced accuracy or velocity. The sensation of fatigue incorporates an elevated rating of perceived exertion (RPE) during submaximal tasks, due to a combination of peripheral and higher CNS inputs. Competition performance (sport symptoms) is affected more by decision-making and psychological aspects, since there are opponents and a greater importance on the result. Laboratory based decision making is generally faster or unimpaired. Motivation, self-efficacy and anxiety can change during exercise to modify RPE and, hence, alter physical performance. Symptoms of fatigue during racing, team-game or racquet sports are largely anecdotal, but sometimes assessed with time-motion analysis. Fatigue during brief all-out racing is described biomechanically as a decline of peak velocity, along with altered kinematic components. Longer sport events involve pacing strategies, central and peripheral fatigue contributions and elevated RPE. During match play, the work rate can decline late in a match (or tournament) and/or transiently after intense exercise bursts. Repeated sprint ability, agility and leg strength become slightly impaired. Technique outcomes, such as velocity and accuracy for throwing, passing, hitting and kicking, can deteriorate. Physical and subjective changes are both less severe in real rather than simulated sport activities. Little objective evidence exists to support exercise-induced mental lapses during sport. A model depicting mind-body interactions during sport competition shows that the RPE centre-motor cortex-working muscle sequence drives overall performance levels and, hence, fatigue symptoms. The sporting outputs from this sequence can be modulated by interactions with muscle afferent and circulatory feedback, psychological and decision-making inputs. Importantly, compensatory processes exist at many levels to protect against performance decrements. Small changes of putative fatigue factors can also be protective. We show that individual fatigue factors including diminished carbohydrate availability, elevated serotonin, hypoxia, acidosis, hyperkalaemia, hyperthermia, dehydration and reactive oxygen species, each contribute to several fatigue symptoms. Thus, multiple symptoms of fatigue can occur simultaneously and the underlying mechanisms overlap and interact. Based on this understanding, we reinforce the proposal that fatigue is best described globally as an exercise-induced decline of performance as this is inclusive of all viewpoints.

Exacerbated potassium-induced paralysis of mouse soleus muscle at 37°C vis-à-vis 25°C: implications for fatigue. K+ -induced paralysis at 37°C.

The main aim was to investigate the effects of raised [K+](o) on contraction of isolated non-fatigued skeletal muscle at 37°C and 25°C to assess the physiological significance of K+ in fatigue. Mouse soleus muscles equilibrated at 25°C had good mechanical stability when temperature was elevated to 37°C. The main findings at 37°C vis-à-vis 25°C were as follows. When [K+](o) was raised from 4 to 7 mM, there was greater twitch potentiation, but no significant difference in peak tetanic force. At 10 mM [K+](o) there was (1) a faster time course for the decline of peak tetanic force, (2) a greater steady-state depression of twitches and tetani, (3) an increase of peak force over 50-200 Hz (whereas it decreased at 25°C), (4) significant tetanus restoration when stimulus pulse duration increased from 0.1 to 0.25 ms and (5) greater depolarisation of layer-2 fibres, with no repolarisation of surface fibres. These combined data strengthen the proposal that a large run-down of the K+ gradient contributes to severe fatigue at physiological temperatures via depolarisation and impaired sarcolemmal excitability. Moreover, terbutaline, a ß(2)-adrenergic agonist, induced a slightly greater and more rapid, but transient, restoration of peak tetanic force at 10 mM [K+](o) at 37°C vis-à-vis 25°C. A right shift of the twitch force-stimulation strength relationship at 10 mM [K+](o) was partially reversed with terbutaline to confer the protective effect. Thus, catecholamines are likely to stimulate the Na+ -K+ pump more powerfully at 37°C to restore excitability and attenuate, but not prevent, the detrimental effects of K+.

Changes of surface and t-tubular membrane excitability during fatigue with repeated tetani in isolated mouse fast- and slow-twitch muscle.

We investigated whether impaired sarcolemmal excitability causes severe fatigue during repeated tetani in isolated mouse skeletal muscle. Slow-twitch soleus or fast-twitch extensor digitorum longus (EDL) muscles underwent intensive stimulation (standard protocol: 125 Hz for 500 ms, every second, parallel plate electrodes, 20 V, 0.1-ms pulses). Interventions with altered stimulation characteristics were tested either on the entire fatigue profile or after 90- to 100-s stimulation. d-tubocurarine did not alter the fatigue profile in soleus thereby eliminating impaired neuromuscular transmission. Lower stimulation frequencies partially restored peak force, especially in soleus. The twitch force-stimulation strength relationship shifted towards higher voltages in both muscle types, with a much larger shift in EDL. Augmenting pulse strength restored tetanic force from 29% (4.4 V) to 79% (20 V), or slowed fatigue in soleus. Increasing pulse duration (0.1 to 1.0 ms) restored tetanic force from 8 to 46% in EDL and from 41 to 90% in soleus; 0.25-ms pulses restored tetanic force to 83% in soleus. Switching from transverse wire to parallel plate stimulation increased tetanic force from 34 to 63%, and fatigue was exacerbated with wires compared with plates in soleus. The combined data suggest that impaired excitability (disrupted action potential generation) within trains is the main contributor ( approximately 50% initial force) to severe fatigue in both muscle types, the surface rather than t-tubular membrane is the main site of impairment during wire stimulation, and extreme fatigue in EDL includes an increased action potential threshold leading to inexcitable fibers. Moreover, mathematical modeling discounts anoxia as the major contributor to fatigue during our stimulation regime in isolated muscles.

Stimulation pulse characteristics and electrode configuration determine site of excitation in isolated mammalian skeletal muscle: implications for fatigue.

We examined whether electrical field stimulation with varying characteristics could excite isolated mammalian skeletal muscle through different sites. Supramaximal (20-V, 0.1-ms) pulse stimulation with transverse wire or parallel plate electrodes evoked similar forces in nonfatigued slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles from mice. d-tubocurarine shifted the twitch force-stimulation strength relationship toward higher pulse strengths with both electrode configurations in soleus muscle, suggesting that weaker pulses excite muscle via neuromuscular transmission. With wire stimulation, movement of the recording electrode along the muscle caused a delay between the stimulus artifact and the peak of the action potential, consistent with action potential propagation along the sarcolemma. TTX abolished all contractions evoked with 20-V, 0.1-ms pulses, suggesting that excitation occurred via voltage-dependent Na+ channels and, hence, muscle action potentials. TTX did not prevent force development with > or = 0.4-ms pulses in soleus or 1-ms pulses in EDL muscle. Furthermore, myoplasmic Ca2+ (i.e., the fura 2 ratio) and sarcomere shortening were greater during tetanic stimulation with 2.0-ms than with 0.5-ms pulses in flexor digitorum brevis fibers from rats. TTX prevented all shortening and Ca2+ release with 0.5-ms, but not 2.0-ms, pulses, indicating that longer pulses can directly trigger Ca2+ release. Hence, proper interpretation of mechanistic studies requires precise understanding of how muscles are excited; otherwise, incorrect conclusions can be made. Using this new understanding, we showed that disrupted propagation of action potentials along the surface membrane is a major cause of fatigue in soleus muscle that is focally and continuously stimulated at 125 Hz.

Lactic acid and exercise performance : culprit or friend?

This article critically discusses whether accumulation of lactic acid, or in reality lactate and/or hydrogen (H+) ions, is a major cause of skeletal muscle fatigue, i.e. decline of muscle force or power output leading to impaired exercise performance. There exists a long history of studies on the effects of increased lactate/H+ concentrations in muscle or plasma on contractile performance of skeletal muscle. Evidence suggesting that lactate/H+ is a culprit has been based on correlation-type studies, which reveal close temporal relationships between intramuscular lactate or H+ accumulation and the decline of force during fatiguing stimulation in frog, rodent or human muscle. In addition, an induced acidosis can impair muscle contractility in non-fatigued humans or in isolated muscle preparations, and several mechanisms to explain such effects have been provided. However, a number of recent high-profile papers have seriously challenged the 'lactic acid hypothesis'. In the 1990s, these findings mainly involved diminished negative effects of an induced acidosis in skinned or intact muscle fibres, at higher more physiological experimental temperatures. In the early 2000s, it was conclusively shown that lactate has little detrimental effect on mechanically skinned fibres activated by artificial stimulation. Perhaps more remarkably, there are now several reports of protective effects of lactate exposure or induced acidosis on potassium-depressed muscle contractions in isolated rodent muscles. In addition, sodium-lactate exposure can attenuate severe fatigue in rat muscle stimulated in situ, and sodium lactate ingestion can increase time to exhaustion during sprinting in humans. Taken together, these latest findings have led to the idea that lactate/H+ is ergogenic during exercise. It should not be taken as fact that lactic acid is the deviant that impairs exercise performance. Experiments on isolated muscle suggest that acidosis has little detrimental effect or may even improve muscle performance during high-intensity exercise. In contrast, induced acidosis can exacerbate fatigue during whole-body dynamic exercise and alkalosis can improve exercise performance in events lasting 1-10 minutes. To reconcile the findings from isolated muscle fibres through to whole-body exercise, it is hypothesised that a severe plasma acidosis in humans might impair exercise performance by causing a reduced CNS drive to muscle.

Multiple effects of caffeine on simulated high-intensity team-sport performance.

INTRODUCTION: Caffeine enhances performance of single bouts of endurance exercise, but its effects on repeated bouts typical of those in high-intensity team sports are unclear. PURPOSE: To investigate effects of caffeine in a performance test simulating physical and skill demands of a rugby union game. METHODS: The study was a double-blind, randomized, crossover design in which nine competitive male rugby players ingested either caffeine (6 mg.kg(-1) body mass) or placebo (dextrose) 70 min before performing a rugby test. Each test consisted of seven circuits in each of two 40-min halves with a 10-min half-time rest. Each circuit included stations for measurement of sprint time (two straight-line and three agility sprints), power generation in two consecutive drives, and accuracy for passing balls rapidly. Interstitial fluid was sampled transdermally by electrosonophoresis before ingestion of caffeine or placebo and then before testing, at half-time, and immediately after testing; samples were assayed chromatographically for caffeine and epinephrine concentrations. RESULTS: The effects of caffeine on mean performance (+/-90% confidence limits) over all 14 circuits were: sprint speeds, 0.5% (+/-1.7%) through 2.9% (+/-1.3%); first-drive power, 5.0% (+/-2.5%); second-drive power, -1.2% (+/-6.8%); and passing accuracy, 9.6% (+/-6.1%). The enhancements were mediated partly through a reduction of fatigue that developed throughout the test and partly by enhanced performance for some measures from the first circuit. Caffeine produced a 51% (+/-11%) increase in mean epinephrine concentration; correlations between individual changes in epinephrine concentration and changes in performance were mostly unclear, but there were some strong positive correlations with sprint speeds and a strong negative correlation with passing accuracy. CONCLUSION: Caffeine is likely to produce substantial enhancement of several aspects of high-intensity team-sport performance.

Changes of motor drive, cortical arousal and perceived exertion following prolonged cycling to exhaustion.

The aims of this study were to (1) quantify any central fatigue that occurs following prolonged dynamic exercise, i.e. reduced muscle force caused by impaired motor drive from the central nervous system and (2) determine whether decreased cortical arousal, assessed using critical flicker fusion threshold (CFF), occurs and is related to impaired exercise performance. Fifteen healthy men cycled at 70% VO2peak until exhaustion. The peak force of maximum voluntary isometric contractions (MVC) of the quadriceps muscle group was reduced by 30% at exhaustion. The voluntary activation ratio determined using superimposed tetanic stimulation fell from 0.99 to 0.86 at exhaustion. The central fatigue (%) at exhaustion was 33+/-12% (+/- SD) (assessed via the tetanus interpolation technique) and 54+/-32% (assessed via the relative decline of MVC and peak tetanic force) of the total fatigue. The MVC only partially recovered and central fatigue persisted at 30 min post-exercise. CFF increased from 39.2+/-2.3 to 41.8+/-3.5 Hz at exhaustion, but did not correlate with central fatigue. Every subject reached the highest rating of perceived exertion (RPE) at exhaustion of 20 on the Borg scale. The time to exhaustion was related to how quickly the RPE increased and to the ability to sustain exercise at very high RPE. These data suggest that with prolonged cycling: (1) there is considerable and a persistent form of central fatigue, (2) there is an increased level of cortical arousal, and (3) exhaustion is linked to very high subjective RPE.