The effect of acid-base balance on fatigue of skeletal muscle

H+ ions are generated rapidly when muscles are maximally activated. This results in an intracellular proton load. Typical proton loads in active muscles reach a level of 20-25 mumol X g-1, resulting in a fall in intracellular pH of 0.3-0.5 units in mammalian muscle and 0.6-0.8 units in frog muscle. In isolated frog muscles stimulated to fatigue a proton load of this magnitude is developed, and at the same time maximum isometric force is suppressed by 70-80%. Proton loss is slowed when external pH is kept low. This is paralleled by a slow recovery of contractile tension and seems to support the idea that suppression results from intracellular acidosis. Nonfatigued muscles subjected to similar intracellular proton loads by high CO2 levels show a suppression of maximal tension by only about 30%. This indicates that only a part of the suppression during fatigue is normally due to the direct effect of intracellular acidosis. Further evidence for a component of fatigue that is not due to intracellular acidosis is provided by the fact that some muscle preparations (rat diaphragm) can be fatigued with very little lactate accumulation and very low proton loads. Even under these conditions, a low external pH (6.2) can slow recovery of tension development 10-fold compared with normal pH (7.4). We must conclude that there are at least two components to fatigue. One, due to a direct effect of intracellular acidosis, acting directly on the myofibrils, accounts for a part of the suppression of contractile force. A second, which in many cases may be the major component, is not dependent on intracellular acidosis. This component seems to be due to a change of state in one or more of the steps of the excitation-contraction coupling process. Reversal of this state is sensitive to external pH which suggests that this component is accessible from the outside of the cell.     

Intracellular pH recovery from lactic acidosis of single skeletal muscle fibers

Intracellular pH (pHi), measured with H+-selective microelectrodes, in quiescent frog sartorius muscle fibres was 7.29 +/- 0.09 (n = 13). Frog muscle fibres were superfused with a modified Ringer solution containing 30 mM HEPES buffer, at extracellular pH (pHo) 7.35. Intracellular pH decreased to 6.45 +/- 0.14 (n = 13) following replacement of 30 mM NaCl with sodium lactate (30 mM MES, pHo 6.20). Intracellular pH recovery, upon removal of external lactic acid, depended on the buffer concentration of the modified Ringer solution. The measured values of the pHi recovery rates was 0.06 +/- 0.01 delta pHi/min (n = 5) in 3 mM HEPES and was 0.18 +/- 0.06 delta pHi/min (n = 13) in 30 mM HEPES, pHo 7.35. The Na+-H+ exchange inhibitor amiloride (2 mM) slightly reduced pHi recovery rate. The results indicate that the net proton efflux from lactic acidotic frog skeletal muscle is mainly by lactic acid efflux and is limited by the transmembrane pH gradient which, in turn, depends on the extracellular buffer capacity in the diffusion limited space around the muscle fibres.     

Effects of depolarization and low intracellular pH on charge movement currents of frog skeletal muscle fibers

The low intracellularpH and membrane depolarization associated with repeated skeletal musclestimulation could impair the function of the transverse tubular (ttubule) voltage sensor and result in a decreased sarcoplasmic reticulumCa²⁺ release and muscle fatigue. We therefore examined theeffects of membrane depolarization and low intracellular pH on thet-tubular charge movement. Fibers were voltage clamped in a doubleVaseline gap, at holding potential (HP) of 90 or 60 mV, and studiedat an internal pH of 7.0 and 6.2. Decreasing intracellular pH did notsignificantly alter the maximum amount of charge moved, transition voltage, or steepness factor at either HP. Depolarizing HPsignificantly decreased steepness factor and maximum charge moved andshifted the transition voltage to more positive potentials. Elevatedextracellular Ca²⁺ decreased the depolarization-inducedreduction in the charge movement. These results indicate that, althoughthe decrease in intracellular pH seen in fatigued muscle does notimpair the t-tubular charge movement, the membrane depolarizationassociated with muscle fatigue may be sufficient to inactivate asignificant fraction of the t-tubular charge. However, if t-tubularCa²⁺ increases, some of the charge may be stabilized in theactive state and remain available to initiate sarcoplasmic reticulum Ca²⁺ release.

     

Role of intracellular pH in muscle fatigue

Intracellular pH of in vitro diaphragm preparations was determined following low- (5 Hz, 1.5 min) and high- (75 Hz, 1 min) frequency stimulation, using glass microelectrodes of the liquid membrane type (pHm). Results were compared with values obtained by the standard homogenate technique (pHh). High- and low-frequency stimulation reduced peak tetanic tension to 21 +/- 1 (SE) and 71 +/- 2% of initial values, respectively. Peak tetanic tension returned to resting values after 10- to 15-min recovery from high- or low-frequency stimulation. Resting pHm was 7.063 +/- 0.011 (n = 72), and after fatiguing stimulation declined to values as low as 6.33. During recovery pHm significantly increased and by 10 min had returned to prefatigue values. No difference was observed in the recovery of pHm between the low- and high-frequency stimulation groups (analysis of variance test, ANOVA), and in both groups pHm recovery was highly correlated to the recovery of peak tetanic tension (r = 0.94, P less than 0.001). Resting pHh was 7.219 +/- 0.023 (n = 13), which was significantly higher than the pHm value. In contrast to pHm, intracellular pHh was significantly higher during recovery from 75- vs. 5-Hz stimulation (P less than 0.05). For both groups pHh increased significantly with time and by 10 min returned to prestimulation values. The ANOVA test demonstrated that pHh values were significantly higher than pHm values during recovery from fatigue. The results from this study support our hypothesis that fatigue from both high- and low-frequency stimulation is at least partially due to the deleterious effects of intracellular acidosis on excitation-contraction coupling.     

Kinetic analysis of the protonation of a surface group of a macromolecule

High-field 31P-NMR studies of whole cells of Streptococcus faecalis have shown that delta pH can be formed by ATP hydrolysis and also by lactate transport. We have used 31P-NMR to measure the pH dependence of the variable stoichiometry of the proton/lactate carrier. At low external pH (pH approximately equal to 6.5) the influx stoichiometry was 1.1 H+/lactate, while at high pH (7.5) the ratio was almost 2; the apparent midpoint pH of this variable stoichiometry is 7. delta psi measurements support the electrogenic nature of lactate transport at high pH; the variable rate of membrane depolarization caused by lactate transport also had a midpoint near pH 7.0. The data is consistent with a symmetrical carrier operating with variable stoichiometry as proposed by Michels et al.     

Effects of β₂-agonists on force during and following anoxia in rat extensor digitorum longus muscle

Electrical stimulation of isolated muscles may lead to membrane depolarization, gain of Na(+), loss of K(+) and fatigue. These effects can be counteracted with β(2)-agonists possibly via activation of the Na(+)-K(+) pumps. Anoxia induces loss of force; however, it is not known whether β(2)-agonists affect force and ion homeostasis in anoxic muscles. In the present study isolated rat extensor digitorum longus (EDL) muscles exposed to anoxia showed a considerable loss of force, which was markedly reduced by the β(2)-agonists salbutamol (10(-6) M) and terbutaline (10(-6) M). Intermittent stimulation (15-30 min) clearly increased loss of force during anoxia and reduced force recovery during reoxygenation. The β(2)-agonists salbutamol (10(-7)-10(-5) M) and salmeterol (10(-6) M) improved force development during anoxia (25%) and force recovery during reoxygenation (55-262%). The effects of salbutamol on force recovery were prevented by blocking the Na(+)-K(+) pumps with ouabain or by blocking glycolysis with 2-deoxyglucose. Dibutyryl cAMP (1 mM) or theophylline (1 mM) also improved force recovery remarkably. In anoxic muscles, salbutamol decreased intracellular Na(+) and increased (86)Rb uptake and K(+) content, indicating stimulation of the Na(+)-K(+) pumps. In fatigued muscles salbutamol induced recovery of excitability. Thus β(2)-agonists reduce the anoxia-induced loss of force, leading to partial force recovery. These data strongly suggest that this effect is mediated by cAMP stimulation of the Na(+)-K(+) pumps and that it is not related to recovery of energy status (PCr, ATP, lactate).     

The effects of pH on the kinetics of fatigue and recovery in frog sartorius muscle

The effects of pH on the kinetics of fatigue and recovery in frog sartorius muscle were studied to establish whether the pH to which muscles are exposed (extracellular pH) has an effect on both the rate of fatigue development and recovery from fatigue. When frog sartorius muscles were stimulated with short tetanic stimuli at rates varying from 0.2 to 2.0 trains/s, a time- and frequency-dependent decrease in force development was observed, but extracellular pH had comparatively little effect. The recovery of tetanic force was dependent on the extracellular pH. This effect was characterized by a rapid recovery in force at pH 8.0 and an inhibition of recovery at pH 6.4 even when force decreased by only 25% during stimulation. Even when muscles were fatigued at pH 8.0 the rate of force recovery was still very small at pH 6.4. A model is proposed in which a step of the contraction cycle changes from a normal to a fatigued state. The rate of this transition is a function of the stimulation frequency and not pH. The reverse transition, from a fatigued to normal state is pH dependent; i.e., it is inhibited by H+. Measurements of resting and action potentials show that extracellular pH influences these parameters in the fatigue state, but there is no evidence that these changes are directly responsible for the pH-dependent step in the reversal of fatigue.     

The role of the synaptic vesicles in transmission at the insect nerve-muscle junction

The ultrastructure of nerve-muscle synapses on red and white fibres of locust ($\text{Schistocerca}$$\text{gregaria}$) retractor unguis muscle fibres was examined before and after stimulation. At a stimulation frequency of 15Hz, the synapses on the white fibres fatigued completely; those on the red fibres also fatigued, but during prolonged stimulation they showed intermittent periods of recovery. Synaptic vesicles at both types of fatigued synapses were reduced in volume compared with controls and at fatigued synapses on white fibres the vesicles had irregular outlines. Aggregation of vesicles were observed at fatigued synapses on red fibres and the synaptic cleft width at these synapses was less than at control synapses on red fibres. These results are discussed in the light of the vesicle hypothesis for synaptic transmission.     

Relationship of contraction capacity to metabolic changes during recovery from a fatiguing contraction

The relationship between changes in muscle metabolites and the contraction capacity was investigated in humans. Subjects (n = 13) contracted (knee extension) at a target force of 66% of the maximal voluntary contraction force (MVC) to fatigue, and the recovery in MVC and endurance (time to fatigue) were measured. Force recovered rapidly [half-time (t 1/2) less than 15 s] and after 2 min of recovery was not significantly different (P greater than 0.05) from the precontraction value. Endurance recovered more slowly (t 1/2 approximately 1.2 min) and was still significantly depressed after 2 and 4 min of recovery (P less than 0.05). In separate experiments (n = 10) muscle biopsy specimens were taken from the quadriceps femoris muscle before and after two successive contractions to fatigue at 66% of MVC with a recovery period of 2 or 4 min in between. The muscle content of high-energy phosphates and lactate was similar at fatigue after both contractions, whereas glucose 6-phosphate was lower after the second contraction (P less than 0.05). During recovery, muscle lactate decreased and was 74 and 43% of the value at fatigue after an elapsed period of 2 and 4 min, respectively. The decline in H+ due to lactate disappearance is balanced, however, by a release of H+ due to resynthesis of phosphocreatine, and after 2 min of recovery calculated muscle pH was found to remain at a low level similar to that at fatigue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Energy recycling by lactate efflux in growing and nongrowing cells of Streptococcus cremoris.

Streptococcus cremoris was grown in pH-regulated batch and continuous cultures with lactose as the energy source. During growth the magnitude and composition of the electrochemical proton gradient and the lactate concentration gradient were determined. The upper limit of the number of protons translocated with a lactate molecule during lactate excretion (the proton-lactate stoichiometry) was calculated from the magnitudes of the membrane potential, the transmembrane pH difference, and the lactate concentration gradient. In cells growing in continuous culture, a low lactate concentration gradient (an internal lactate concentration of 35 to 45 mM at an external lactate concentration of 25 mM) existed. The cell yield (Ymax lactose) increased with increasing growth pH. In batch culture at pH 6.34, a considerable lactate gradient (more than 60 mV) was present during the early stages of growth. As growth continued, the electrochemical proton gradient did not change significantly (from -100 to -110 mV), but the lactate gradient decreased gradually. The H+-lactate stoichiometry of the excretion process decreased from 1.5 to about 0.9. In nongrowing cells, the magnitude and composition of the electrochemical proton gradient was dependent on the external pH but not on the external lactate concentration (up to 50 mM). The magnitude of the lactate gradient was independent of the external pH but decreased greatly with increasing external lactate concentrations. At very low lactate concentrations, a lactate gradient of 100 mV existed, which decreased to about 40 mV at 50 mM external lactate. As a consequence, the proton-lactate stoichiometry decreased with increasing external concentrations of protons and lactate at pH 7.0 from 1 mM lactate to 1.1 at 50 mM lactate and at pH 5.5 from 1.4 at l mM lactate to 0.7 at 50 mM lactate. The data presented in this paper suggest that a decrease in external pH and an increase in external lactate concentration both result in lower proton-lactate stoichiometry values and therefore in a decrease of the generation of metabolic energy by the end product efflux process.     

Electromyographic changes in the isolated rat diaphragm during the development of fatigue

To investigate whether the power spectrum of the electromyogram of a fatiguing muscle can be used to infer the degree to which the muscle is fatigued, we recorded isometric tension and two monopolar electromyograms from eight isolated rat diaphragm preparations suspended in an organ bath containing a balanced salt solution. Each preparation was excited with a fixed phrenic nerve impulse pattern made up of a 70-Hz train of impulses of supramaximal voltage delivered for 170 ms with a 500-ms recovery period. Tension fell rapidly over the first 60 s of the fatigue run and more slowly for the remaining 60 s analysed. The duration of extracellular action potentials increased and their amplitude decreased as the tension developed by the diaphragm decreased; conduction velocity along muscle fibres also decreased. The centroid frequency (fcen) of the power spectrum of the first action potential elicited by each train of stimuli decreased rapidly until tension fell to approximately 70% of the initial value; thereafter little change in fcen occurred, although tension continued to fall to 33% of its initial value. Our results demonstrated that under controlled conditions, fcen provided a sensitive index of fatigue in its early stages, but provided no information once fatigue was pronounced.     

Cardiovascular limitations of active recovery from strenuous exercise.

Recovery from muscle fatigue after exercise is known to have two beneficial effects: improved blood lactate elimination and a central nervous recuperation of the capacity for exercise. This study indicates circulatory mechanisms that might limit active recovery. Ten subjects were seated on a cycle ergometer and performed arm cranking exercise at an anaerobic intensity which was for each individual in three periods of 6 min, alternating with recovery intervals of 14 min. In two randomly assigned tests, recovery consisted either of passive sitting (control) or cycling at 80 W for 12 min. Both tests terminated with an identical final passive rest period of 25 min. In the cycling test arm cranking led to a heart rate increase which was further elevated with each repetition, while in the control test no differences were shown among the cranking periods. No corresponding difference was found for oxygen consumption. During the 25 min of final rest, the cycling test showed arterial hypotension and elevated heart rate both of which were absent in the control tests. Venous-occlusion-plethysmography revealed a postcranking forearm hyperaemia. In the cycling test hyperaemia was markedly reduced with the onset of cycling due to vasoconstriction; this effect was absent in the control test. A reduction in blood lactate occurred faster in the cycling test, mainly at the onset of cycling. Total plasma fluid loss combined with forearm fluid uptake was accentuated and prolonged by cycling recovery. Recovery exercise performed by muscles other than those that were fatigued could have led to arterial hypotension (shock-index about 1) through both plasma fluid loss and additional vasodilatation depending on the muscle mass involved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of sulfhydryl inhibitors on depolarizations-contraction coupling in frog skeletal muscle fibers

We have studied the effects of the sulfhydryl reagents on contractile responses, using either electrically stimulated single muscle fibers or short muscle fibers that were voltage-clamped with a two-microelectrode voltage-clamp technique that allows the fiber tension in response to membrane depolarization to be recorded. The sulfhydryl inhibitors para- chloromercuribenzoic acid (PCMB) and parahydroximercuriphenyl sulfonic acid (PHMPS), at concentrations from 0.5 to 2 mM, cause loss of the contractile ability; however, before this effect is completed, they change the fiber contractile behavior in a complex way. After relatively short exposure to the compounds, < 20 min, before the fibers lose their contractile capacity, secondary tension responses may appear after electrically elicited twitches or tetani. After losing their ability to contract in response to electrical stimulation, the fibers maintain their capacity to develop caffeine contractures, even after prolonged periods (120 min) of exposure to PHMPS. In fibers under voltage-clamp conditions, contractility is also lost; however, before this happens, long-lasting (i.e., minutes) episodes of spontaneous contractile activity may occur with the membrane polarized at -100 mV. After more prolonged exposure (> 30 min), the responses to membrane depolarization are reduced and eventually disappear. The agent DTT at a concentration of 2 mM appears to protect the fibers from the effects of PCMB and PHMPS. Furthermore, after loss of the contractile responses by the action of PCMB or PHMPS, addition of 2 mM DTT causes recovery of tension development capacity.     

Modulation of the Plasma Membrane Electron Transfer System in Root Cells of Limnobium stoloniferum by External pH

The influence of ferricyanide on transmembrane electron transfer,proton secretion, membrane potential, and cytoplasmic pH ofLimnobium stoloniferum (G.F. Mey) Griseb. root cells was investigatedat different external pH HCF III reduction by the roots was accompanied by membrane depolarization,an increase in proton secretion and by alkalinization of thecytoplasm. Change of membrane potential and cytoplasmic pH aswell as transmembrane e^– transfer was more pronouncedat acid external pH. The rate of proton flux was linearly dependenton the rate of electron transfer. The slope of the relationshipwas around 1, independent of external pH The data are in agreement with the hypothesis that electrontransfer at the plasma membrane is directly coupled to protonsecretion. It is suggested that both e^– and redox-coupledH⁺ transport are activated by acid external pH Key words: Plasmalemma redox system, electron transfer, proton transport, pH, membrane potential, Limnobium stoloniferum     

Excitation-induced cell damage and beta2-adrenoceptor agonist stimulated force recovery in rat skeletal muscle

Intensive exercise leads to a loss of force, which may be long lasting and associated with muscle cell damage. To simulate this impairment and to develop means of compensating the loss of force, extensor digitorum longus muscles from 4-wk-old rats were fatigued using intermittent 40-Hz stimulation (10 s on, 30 s off). After stimulation, force recovery, cell membrane leakage, and membrane potential were followed for 240 min. The 30-60 min of stimulation reduced tetanic force to approximately 10% of the prefatigue level, followed by a spontaneous recovery to approximately 20% in 120-240 min. Loss of force was associated with a decrease in K+ content, gain of Na+ and Ca2+ content, leakage of the intracellular enzyme lactic acid dehydrogenase (10-fold increase), and depolarization (13 mV). Stimulation of the Na+-K+ pump with either the beta2-adrenoceptor agonist salbutamol, epinephrine, rat calcitonin gene-related peptide (rCGRP), or dibutyryl cAMP improved force recovery by 40-90%. The beta-blocker propranolol abolished the effect of epinephrine on force recovery but not that of CGRP. Both spontaneous and salbutamol-induced force recovery were prevented by ouabain. The salbutamol-induced force recovery was associated with repolarization of the membrane potential (12 mV) to the level measured in unfatigued muscles. In conclusion, in muscles exposed to fatiguing stimulation leading to a considerable loss of force, cell leakage, and depolarization, stimulation of the Na+-K+ pump induces repolarization and improves force recovery, possibly due to the electrogenic action of the Na+-K+ pump. This mechanism may be important for the restoration of muscle function after intense exercise.     

Membrane potential,pH and the activation of surf clam oocytes

Unfertilized oocytes of the surf clam, Spisula solidissima, have resting membrane potentials of ?18 ± 7 mV (n = 20). Within five seconds of sperm addition, an electrophysiologically detectable response was apparent, which was characterized by a rapid and prolonged depolarrization depolarization followed four to five minutes post-insemination by the beginning of the beginning of a steady hyperpolarization to approximatelv ?70 mV. This final hyperpolarization was completed within ten minutes of sperm addition. The initial rapid depolarization following insemination may result from a transient increase in sodium conductance, and it may be crucial in preventing polyspermy, since the degree of polyspermy in Spisula oocytes was sensitive to external sodium ion concentrations. Evidence was obtained that changes in intracellular pH are essential for oocvte activation. Using germinal vesical breakdown (GVB) as a marker for activation, it was shown that agents that raise intracellular pH (ammonia and procaine) induced GVB, whereas agents that lower intracellular pH pH (Na-acetate or Na-propionate seawater) inhibited GVB.     

Cell volume regulation of cerebrovascular endothelium in vitro

Regulation of cell volume as a fundamental cellular function of high biological priority was studied in cultured cerebrovascular endothelium. The use of a multiparameter flow cytometric system allowed simultaneous measurements of cell volume, viability, and membrane potential or intracellular pH. Endothelium, the cellular constituent of the blood-brain barrier (BBB), swells immediately on exposure to low osmolality. This is associated with membrane depolarization and a fall of intracellular pH. Within 30-60 min, cell volume and membrane potential recover completely, although the extracellular osmolality is kept low. Intracellular pH does not normalize fully. Measurements of intracellular K+ and Na+ concentrations reveal their involvement in the regulatory process. The findings strongly suggest that the cerebrovascular endothelium has a highly effective built-in capacity for homeostatic control essential for normal BBB function.     

Single motor unit and fiber action potentials during fatigue

Muscle fatigue is defined as a loss of tension development during constant stimulation. Although the relationship is not well documented, muscle fatigue has been inferred from electromyogram (EMG) signals. The purpose of this study was to determine the relationship between the amplitude and duration of single motor unit action potentials (MUAPs) and the loss of tension development (fatigue) in the medial gastrocnemius muscles of cats. Single motor units were fatigued by continuous stimulation at 10 or 80 Hz or with trains of 40-Hz stimuli. When motor units were stimulated at 10 Hz and with trains at 40 Hz (low frequency), tension declined and remained depressed during recovery. The changes in the MUAP correlated poorly with changes in tension. During and after stimulation at 80 Hz (high frequency), changes in the amplitude and duration of MUAPs correlated highly with changes in tension development. Since the EMG signal is dependent on a summation and cancellation of individual MUAPs, the EMG provides a reasonable estimate of high-frequency fatigue but an unreliable measure of low-frequency fatigue.     

Substrate-dependent proton load and recovery of stunned hearts during pyruvate dehydrogenase stimulation

Stimulation of pyruvate dehydrogenase (PDH) improves functional recovery of postischemic hearts. This study examined the potential for a mechanism mediated by substrate-dependent proton production and intracellular pH. After 20 min of ischemia, isolated rabbit hearts were reperfused with or without 5 mM dichloroacetate (DCA) in the presence of either 5 mM glucose, 5 mM glucose + 2.5 mM lactate, or 5 mM glucose + 2.5 mM pyruvate. DCA inhibits PDH kinase, increasing the proportion of dephosphorylated, active PDH. Unlike pyruvate or glucose alone, lactate + glucose did not support the effects of DCA on the recovery of rate-pressure product (RPP) (without DCA, RPP = 14,000 +/- 1,200, n = 6; with DCA, RPP = 13,700 +/- 1,800, n = 9). Intracellular pH, from (31)P nuclear magnetic resonance spectra, returned to normal within 2.1 min of reperfusion with all substrates except for lactate + glucose + DCA or lactate + DCA, which delayed pH recovery for up to 12 min (at 2.1 min pH = 6. 00 +/- 0.08, lactate + glucose + DCA; pH = 6.27 +/- 0.34, for lactate + DCA). Hearts were also reperfused after 10 min of ischemia with 0.5 mM palmitate + 5 mM DCA and either 2.5 mM pyruvate or 2.5 mM lactate. Again, intracellular pH recovery was delayed in the presence of lactate. PDH activation in the presence of lactate also decreased coupling of oxidative metabolism to mechanical work. These findings have implications for therapeutic use of stimulated carbohydrate oxidation in stunned hearts.     

Electro-mechanical failures and lactate production during fatigue

The electrical and mechanical failures observed during sustained and intermittent electrically triggered (30 Hz) contractions of human flexor carpi ulnaris were compared with the blood lactate concentration. The changes recorded during contractions sustained for 60 s were compared with those observed during a series of sixty 1 s contractions separated by 1 s intervals, and also with the changes during the first 30 min of recovery. No significant (P less than 0.05) difference in force reduction or maximal venous lactate concentration was observed in either fatigue test, although electrical failure differed significantly (P less than 0.05). The recovery of electrical failure was poorly correlated with the reduction in lactate concentration following both sustained (r = -0.70) and intermittent contractions (r = 0.72). In contrast, the recovery in tetanic tension, rate of tension development and time to half relaxation correlated closely with the reduction in venous lactate concentration (r = -0.95, -0.93 and 0.96 respectively). It is suggested that, of the peripheral processes which appear to play a dominant role in peripheral fatigue, lactate production controls mechanical failure directly.