Simeon P. Cairns

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.

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.

Do multiple ionic interactions contribute to skeletal muscle fatigue

During intense exercise or electrical stimulation of skeletal muscle the concentrations of several ions change simultaneously in interstitial, transverse tubular and intracellular compartments. Consequently the functional effects of multiple ionic changes need to be considered together. A diminished transsarcolemmal K+ gradient per se can reduce maximal force in non‐fatigued muscle suggesting that K+ causes fatigue. However, this effect requires extremely large, although physiological, K+ shifts. In contrast, moderate elevations of extracellular [K+] ([K+]o) potentiate submaximal contractions, enhance local blood flow and influence afferent feedback to assist exercise performance. Changed transsarcolemmal Na+, Ca2+, Cl− and H+ gradients are insufficient by themselves to cause much fatigue but each ion can interact with K+ effects. Lowered Na+, Ca2+ and Cl− gradients further impair force by modulating the peak tetanic force–[K+]o and peak tetanic force–resting membrane potential relationships. In contrast, raised [Ca2+]o, acidosis and reduced Cl− conductance during late fatigue provide resistance against K+‐induced force depression. The detrimental effects of K+ are exacerbated by metabolic changes such as lowered [ATP]i, depleted carbohydrate, and possibly reactive oxygen species. We hypothesize that during high‐intensity exercise a rundown of the transsarcolemmal K+ gradient is the dominant cellular process around which interactions with other ions and metabolites occur, thereby contributing to fatigue.

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.

Double-sigmoid model for fitting fatigue profiles in mouse fast- and slow-twitch muscle.

We present a curve‐fitting approach that permits quantitative comparisons of fatigue profiles obtained with different stimulation protocols in isolated slow‐twitch soleus and fast‐twitch extensor digitorum longus (EDL) muscles of mice. Profiles from our usual stimulation protocol (125 Hz for 500 ms, evoked once every second for 100–300 s) could be fitted by single‐term functions (sigmoids or exponentials) but not by a double exponential. A clearly superior fit, as confirmed by the Akaiki Information Criterion, was achieved using a double‐sigmoid function. Fitting accuracy was exceptional; mean square errors were typically <1% and r2 > 0.9995. The first sigmoid (early fatigue) involved ∼10% decline of isometric force to an intermediate plateau in both muscle types; the second sigmoid (late fatigue) involved a reduction of force to a final plateau, the decline being 83% of initial force in EDL and 63% of initial force in soleus. The maximal slope of each sigmoid was seven‐ to eightfold greater in EDL than in soleus. The general applicability of the model was tested by fitting profiles with a severe force loss arising from repeated tetanic stimulation evoked at different frequencies or rest periods, or with excitation via nerve terminals in soleus. Late fatigue, which was absent at 30 Hz, occurred earlier and to a greater extent at 125 than 50 Hz. The model captured small changes in rate of late fatigue for nerve terminal versus sarcolemmal stimulation. We conclude that a double‐sigmoid expression is a useful and accurate model to characterize fatigue in isolated muscle preparations.

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.

Logarithmic superposition of force response with rapid length changes in relaxed porcine airway smooth muscle

We present a systematic quantitative analysis of power-law force relaxation and investigate logarithmic superposition of force response in relaxed porcine airway smooth muscle (ASM) strips in vitro. The term logarithmic superposition describes linear superposition on a logarithmic scale, which is equivalent to multiplication on a linear scale. Additionally, we examine whether the dynamic response of contracted and relaxed muscles is dominated by cross-bridge cycling or passive dynamics. The study shows the following main findings. For relaxed ASM, the force response to length steps of varying amplitude (0.25-4% of reference length, both lengthening and shortening) are well-fitted with power-law functions over several decades of time (10⁻² to 10³ s), and the force response after consecutive length changes is more accurately fitted assuming logarithmic superposition rather than linear superposition. Furthermore, for sinusoidal length oscillations in contracted and relaxed muscles, increasing the oscillation amplitude induces greater hysteresivity and asymmetry of force-length relationships, whereas increasing the frequency dampens hysteresivity but increases asymmetry. We conclude that logarithmic superposition is an important feature of relaxed ASM, which may facilitate a more accurate prediction of force responses in the continuous dynamic environment of the respiratory system. In addition, the single power-function response to length changes shows that the dynamics of cross-bridge cycling can be ignored in relaxed muscle. The similarity in response between relaxed and contracted states implies that the investigated passive dynamics play an important role in both states and should be taken into account.

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

Our aim is to describe the acute effects of catecholamines/β‐adrenergic agonists on contraction of non‐fatigued skeletal muscle in animals and humans, and explain the mechanisms involved. Adrenaline/β‐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. β2‐Adrenoceptor stimulation activates distinct cyclic AMP‐dependent protein kinases to phosphorylate multiple target proteins. β‐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 Ca2+ sensitivity and maximum Ca2+‐activated force are unchanged. All force potentiation involves amplified myoplasmic Ca2+ transients consequent to increased Ca2+ release from sarcoplasmic reticulum (SR). This unequivocally requires phosphorylation of SR Ca2+ release channels/ryanodine receptors (RyR1) which sensitize the Ca2+‐induced Ca2+ release mechanism. Enhanced trans‐sarcolemmal Ca2+ influx through phosphorylated voltage‐activated Ca2+ channels contributes to force potentiation in diaphragm and amphibian muscle, but not mammalian limb muscle. Phosphorylation of phospholamban increases SR Ca2+ pump activity in slow‐twitch fibres but does not augment force; this process accelerates relaxation and may depress force. Greater Ca2+ 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 β‐agonist concentration used. Indeed high‐dose β‐agonists (∼0.1 μm) enhance SR Ca2+‐release rates, maximum voluntary contraction strength and peak Wingate power in trained humans. The combined findings can explain how adrenaline/β‐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.

Holistic approaches to understanding mechanisms of fatigue in high-intensity sport

Purpose: The purpose of this article is to provide a holistic understanding of likely mechanisms of fatigue during high-intensity sports lasting 1–10 min. Methods: The contributions from skeletal muscle, central nervous system (motor drive), and fatigue sensations to lower performance during intense cycling, running, rowing, repeated sprints, or knee extensions were evaluated. Results: At the end of exercise, reductions of external power, force, or velocity and peak isometric forces are moderate (10–30%), motor drive falls by <8%, and fatigue sensations are extreme, e.g., Borgs rating of perceived exertion >18. Multiple putative fatigue factors can change simultaneously to interactively lower performance and/or provide protection. Major detrimental factors include raised intramuscular inorganic phosphate, severe extra- and intracellular acidosis, cerebral hypoxemia, large reduction of trans-sarcolemmal K+-gradient (also Na+- and Cl−-gradients), and reduced muscle glycogen levels. Factors resisting fatigue include elevated adrenaline, extracellular lactate, interstitial [H+] and [K+], and a normal trans-sarcolemmal Cl−-gradient. Conclusions: Raised inorganic phosphate interacting with intracellular H+, and a large rundown of trans-sarcolemmal ion gradients are likely to cause peripheral fatigue. Severe arterial hypoxemia (due to plasma acidosis, raised core temperature, lowered PaO2), and factors released from glycogen lowered muscles, e.g., interleukin-6, may cause central fatigue and strong fatigue sensations.