Human muscle fatigue after glycogen depletion: a 31P magnetic resonance study.

To differentiate the effects of high energy phosphates, pH, and [H2PO4-] on skeletal muscle fatigue, intracellular acidosis during handgrip exercise was attenuated by prolonged submaximal exercise. Healthy human subjects (n = 6) performed 5-min bouts of maximal rhythmic handgrip (RHG) before (CONTROL) and after prolonged (60-min) handgrip exercise (ATTEN-EX) designed to attenuate lactic acidosis in active muscle by partially depleting muscle glycogen. Concentrations of free intracellular phosphocreatine ([PCr]), adenosine triphosphate ([ATP]), and orthophosphate ([P(i)]) and pH were measured by 31P nuclear magnetic resonance spectroscopy and used to calculate adenosine diphosphate [ADP], [H2PO4-], and [HPO4(2-)]. Handgrip force output was measured with a dynamometer, and fatigue was determined by loss of maximal contractile force. After ATTEN-EX, the normal exercise-induced muscle acidosis was reduced. At peak CONTROL RHG, pH fell to 6.3 +/- 0.1 (SE) and muscle fatigue was correlated with [PCr] (r = 0.83), [P(i)] (r = 0.82), and [H2PO4-] (r = 0.81); [ADP] was 22.0 +/- 5.7 mumol/kg. At peak RHG after ATTEN-EX, pH was 6.9 +/- 0.1 and [ADP] was 116.1 +/- 18.2 mumol/kg, although [PCr] and [P(i)] were not different from CONTROL RHG (P greater than 0.05). After ATTEN-EX, fatigue correlated most closely with [ADP] (r = 0.84). The data indicate that skeletal muscle fatigue 1) is multifactorial, 2) can occur without decreased pH or increased [H2PO4-], and 3) is correlated with [ADP] after exercise-induced glycogen depletion.     

Biochemical adaptations to training: implications for resisting muscle fatigue

Skeletal muscle activity is invariably associated with a decline in force-generating capacity (fatigue). The build-up of metabolic by-products such as intracellular H+ and inorganic phosphate (Pi) has been shown to be one of the potential mechanisms of muscle fatigue. The use of phosphorus magnetic resonance spectroscopy is a repeatable and useful tool to study the effect of pH and Pi on force development. When maximal exercise is preceded by submaximal exercise to reduce the starting muscle pH and increase Pi, the degree of muscle fatigue correlates more strongly with H2PO4- than pH or Pi alone. However, other studies in humans have found that H2PO4- does not always correlate well with fatigue. The use of ramp exercise protocols allow repeatable and sensitive measurement of changes in muscle metabolism in response to endurance training. Chronic electrical stimulation in dogs and endurance training in humans results in reduced pH and Pi changes at the same exercise intensities. This means that the effect of pH and Pi in depressing force development is reduced, which could partially explain the increased fatigue resistance seen following endurance training.     

Effects of progressive exercise and hypoxia on human muscle sarcoplasmic reticulum function.

This study examined the effects of progressive exercise to fatigue in normoxia (N) on muscle sarcoplasmic reticulum (SR) Ca(2+) cycling and whether alterations in SR Ca(2+) cycling are related to the blunted peak mechanical power output (PO(peak)) and peak oxygen consumption (Vo(2 peak)) observed during progressive exercise in hypoxia (H). Nine untrained men (20.7 +/- 0.42 yr) performed progressive cycle exercise to fatigue on two occasions, namely during N (inspired oxygen fraction = 0.21) and during H (inspired oxygen fraction = 0.14). Tissue extracted from the vastus lateralis before exercise and at power output corresponding to 50 and 70% of Vo(2 peak) (as determined during N) and at fatigue was used to investigate changes in homogenate SR Ca(2+)-cycling properties. Exercise in H compared with N resulted in a 19 and 21% lower (P < 0.05) PO(peak) and Vo(2 peak), respectively. During progressive exercise in N, Ca(2+)-ATPase kinetics, as determined by maximal activity, the Hill coefficient, and the Ca(2+) concentration at one-half maximal activity were not altered. However, reductions with exercise in N were noted in Ca(2+) uptake (before exercise = 357 +/- 29 micromol x min(-1) x g protein(-1); at fatigue = 306 +/- 26 micromol x min(-1) x g protein(-1); P < 0.05) when measured at free Ca(2+) concentration of 2 microM and in phase 2 Ca(2+) release (before exercise = 716 +/- 33 micromol x min(-1) x g protein(-1); at fatigue = 500 +/- 53 micromol x min(-1) x g protein(-1); P < 0.05) when measured in vitro in whole muscle homogenates. No differences were noted between N and H conditions at comparable power output or at fatigue. It is concluded that, although structural changes in SR Ca(2+)-cycling proteins may explain fatigue during progressive exercise in N, they cannot explain the lower PO(peak) and Vo(2 peak) observed during H.     

Surface EMG power spectrum and intramuscular pH in human vastus lateralis muscle during dynamic exercise

The relationship between intramuscular pH and the frequency components of the surface electromyographic (EMG) power spectrum from the vastus lateralis muscle was studied in eight healthy male subjects during brief dynamic exercise. The studies were carried out in placebo control and metabolic alkalosis induced by oral administration of NaHCO3. At the onset of exercise, blood pH was 0.08 units higher in alkalosis compared with placebo. Muscle lactate accumulation during exercise was higher in alkalosis (32 +/- 5 mmol/kg wet wt) than in placebo (17 +/- 4 mmol/kg wet wt), but no difference in intramuscular pH was found between the two conditions. The EMG power spectrum was shifted toward lower frequencies during fatigue in the control condition (10.1 +/- 0.9%), and these spectral shifts, evaluated from changes in the mean power frequency (MPF) of the EMG power spectrum, were further accentuated in alkalosis (19 +/- 2%). Although the changes in frequency components of EMG correlated with muscle lactate accumulation (r = 0.68, P less than 0.01), no direct relationship with muscle pH was observed. We conclude that alkalosis results in a greater reduction in MPF associated with a higher muscle lactate accumulation. However, the good correlation observed between the two variables is not likely causative, and a dissociation between intramuscular pH and the increase in the low-frequency content of EMG power spectrum appears during muscle fatigue.     

Human skeletal muscle responses vary with age and gender during fatigue due to incremental isometric exercise.

The purpose of this study was to compare the magnitude and mechanisms of ankle dorsiflexor muscle fatigue in 20 young (33 +/- 6 yr, mean +/- SD) and 21 older (75 +/- 6 yr) healthy men and women of similar physical activity status. Noninvasive measures of central and peripheral (neuromuscular junction, sarcolemma) muscle activation, muscle contractile function, and intramuscular energy metabolism were made before, during, and after incremental isometric exercise. Older subjects fatigued less than young (P < 0.01); there was no effect of gender on fatigue (P = 0.24). For all subjects combined, fatigue was modestly related to preexercise strength (r = 0.49, P < 0.01). Neither central (central activation ratio) nor peripheral (compound muscle action potential) activation played a significant role in fatigue in any group. During exercise, intracellular concentrations of P(i) and H(2)PO increased more and pH fell more in young compared with older subjects (P < 0.01) and in men compared with women (P < 0.01). These varied metabolic responses to exercise suggest a greater reliance on nonoxidative sources of ATP in young compared with older subjects and in men compared with women. These results suggest that the mechanisms of fatigue vary with age and gender, regardless of whether differences in the magnitude of fatigue are observed.     

Neural and metabolic mechanisms of excessive muscle fatigue in maintenance hemodialysis patients

Dialysis patients have severe exercise limitations related to metabolic disturbances, but muscle fatigue has not been well studied in this population. We investigated the magnitude and mechanisms of fatigue of the ankle dorsiflexor muscles in patients on maintenance hemodialysis. Thirty-three dialysis patients and twelve healthy control subjects performed incremental isometric dorsiflexion exercise, beginning at 10% of their maximal voluntary contraction (MVC) and increasing by 10% every 2 min. Muscle fatigue (fall of MVC), completeness of voluntary activation, and metabolic responses to exercise were measured. Before exercise, dialysis subjects exhibited reduced strength and impaired peripheral activation (lower compound muscle activation potential amplitude) but no metabolic perturbation. During exercise, dialysis subjects demonstrated threefold greater fatigue than controls with evidence of central activation failure but no change in peripheral activation. All metabolic parameters were significantly more perturbed at end exercise in dialysis subjects than in controls, including lower phosphocreatine (PCr) and pH, and higher P(i), P(i)/PCr, and H(2)PO(4)(-). Oxidative potential was markedly lower in patients than in controls [62.5 (SD 27.2) vs. 134.6 (SD 31.7), P < 0.0001]. Muscle fatigue was negatively correlated with oxidative potential among dialysis subjects (r = -0.52, P = 0.04) but not controls. Changes in central activation ratio were also correlated with muscle fatigue in the dialysis subjects (r = 0.59, P = 0.001) but not the controls. This study provides new information regarding the excessive muscular fatigue of dialysis patients and demonstrates that the mechanisms of this fatigue include both intramuscular energy metabolism and central activation failure.     

Locomotor muscle fatigue increases cardiorespiratory responses and reduces performance during intense cycling exercise independently from metabolic stress

Locomotor muscle fatigue, defined as an exercise-induced reduction in maximal voluntary force, occurs during prolonged exercise, but its effects on cardiorespiratory responses and exercise performance are unknown. In this investigation, a significant reduction in locomotor muscle force (-18%, P < 0.05) was isolated from the metabolic stress usually associated with fatiguing exercise using a 100-drop-jumps protocol consisting of one jump every 20 s from a 40-cm-high platform. The effect of this treatment on time to exhaustion during high-intensity constant-power cycling was measured in study 1 (n = 10). In study 2 (n = 14), test duration (871 +/- 280 s) was matched between fatigue and control condition (rest). In study 1, locomotor muscle fatigue caused a significant curtailment in time to exhaustion (636 +/- 278 s) compared with control (750 +/- 281 s) (P = 0.003) and increased cardiac output. Breathing frequency was significantly higher in the fatigue condition in both studies despite similar oxygen consumption and blood lactate accumulation. In study 2, high-intensity cycling did not induce further fatigue to eccentrically-fatigued locomotor muscles. In both studies, there was a significant increase in heart rate in the fatigue condition, and perceived exertion was significantly increased in study 2 compared with control. These results suggest that locomotor muscle fatigue has a significant influence on cardiorespiratory responses and exercise performance during high-intensity cycling independently from metabolic stress. These effects seem to be mediated by the increased central motor command and perception of effort required to exercise with weaker locomotor muscles.     

Phosphorylating pathways and fatigue development in contracting Xenopus single skeletal muscle fibers

To investigate the differential contribution of oxidative and substrate-level phosphorylation to force production during repetitive, maximal tetanic contractions, single skeletal muscle fiber performance was examined under conditions of high-oxygen availability and anoxia. Tetanic force development (P) was measured in isolated, single type-1 muscle fibers (fast twitch; n = 6) dissected from Xenopus lumbrical muscle while being stimulated at increasing frequencies (0.25, 0.33, and 0.5 Hz), with each frequency lasting 2 min. Two separate work bouts were conducted, with the perfusate PO(2) being either 0 or 159 mmHg. No significant (P < 0. 05) difference was found in the initial peak tensions (P(0)) between the high (334 +/- 57 kPa) and the low (325 +/- 41 kPa) PO(2) treatment. No significant difference in P was observed between the treatments during the first 50 s. However, a significant difference in force production was observed between the high (P/P(0) = 0.96 +/- 0.02) and the low PO(2) condition (P/P(0) = 0.92 +/- 0.02) by 60 s of work. After 60 s, steady-state force production was maintained during the high compared with the low PO(2) condition until stimulation frequency was increased, at which point developed tension during the high PO(2) condition began to decline. Time to fatigue (P/P(0) = 0.3) was reached significantly sooner during the low (250 +/- 16 s) than the high PO(2) condition (367 +/- 28 s). These results demonstrate that during the first 50 s of 0.25-Hz contractions, substrate-level phosphorylation has the capacity to maintain force and ATP hydrolysis when oxidative phosphorylation is absent. This period was followed by an oxygen-dependent phase in which force generation was maintained during the high PO(2) condition (but not during the low PO(2) condition) until the onset of a final fatiguing phase, at which a calculated maximal rate of oxidative phosphorylation was reached.     

Inactivation of human muscle Na+-K+-ATPase in vitro during prolonged exercise is increased with hypoxia.

This study investigated the effects of prolonged exercise performed in normoxia (N) and hypoxia (H) on neuromuscular fatigue, membrane excitability, and Na+-K+ -ATPase activity in working muscle. Ten untrained volunteers [peak oxygen consumption (Vo2peak) = 42.1 +/- 2.8 (SE) ml x kg(-1) x min(-1)] performed 90 min of cycling during N (inspired oxygen fraction = 0.21) and during H (inspired oxygen fraction = 0.14) at approximately 50% of normoxic Vo2peak. During N, 3-O-methylfluorescein phosphatase activity (nmol x mg protein(-1) x h(-1)) in vastus lateralis, used as a measure of Na+-K+-ATPase activity, decreased (P < 0.05) by 21% at 30 min of exercise compared with rest (101 +/- 53 vs. 79.6 +/- 4.3) with no further reductions observed at 90 min (72.8 +/- 8.0). During H, similar reductions (P < 0.05) were observed during the first 30 min (90.8 +/- 5.3 vs. 79.0 +/- 6.3) followed by further reductions (P < 0.05) at 90 min (50.5 +/- 3.9). Exercise in N resulted in reductions (P < 0.05) in both quadriceps maximal voluntary contractile force (MVC; 633 +/- 50 vs. 477 +/- 67 N) and force at low frequencies of stimulation, namely 10 Hz (142 +/- 16 vs. 86.7 +/- 10 N) and 20 Hz (283 +/- 32 vs. 236 +/- 31 N). No changes were observed in the amplitude, duration, and area of the muscle compound action potential (M wave). Exercise in H was without additional effect in altering MVC, low-frequency force, and M-wave properties. It is concluded that, although exercise in H resulted in a greater inactivation of Na+-K+-ATPase activity compared with N, neuromuscular fatigue and membrane excitability are not differentially altered.     

Effect of exercise-induced arterial hypoxemia on quadriceps muscle fatigue in healthy humans

The effect of exercise-induced arterial hypoxemia (EIAH) on quadriceps muscle fatigue was assessed in 11 male endurance-trained subjects [peak O2 uptake (VO2 peak) = 56.4 +/- 2.8 ml x kg(-1) x min(-1); mean +/- SE]. Subjects exercised on a cycle ergometer at >or=90% VO2 peak) to exhaustion (13.2 +/- 0.8 min), during which time arterial O2 saturation (Sa(O2)) fell from 97.7 +/- 0.1% at rest to 91.9 +/- 0.9% (range 84-94%) at end exercise, primarily because of changes in blood pH (7.183 +/- 0.017) and body temperature (38.9 +/- 0.2 degrees C). On a separate occasion, subjects repeated the exercise, for the same duration and at the same power output as before, but breathed gas mixtures [inspired O2 fraction (Fi(O2)) = 0.25-0.31] that prevented EIAH (Sa(O2) = 97-99%). Quadriceps muscle fatigue was assessed via supramaximal paired magnetic stimuli of the femoral nerve (1-100 Hz). Immediately after exercise at Fi(O2) 0.21, the mean force response across 1-100 Hz decreased 33 +/- 5% compared with only 15 +/- 5% when EIAH was prevented (P < 0.05). In a subgroup of four less fit subjects, who showed minimal EIAH at Fi(O2) 0.21 (Sa(O2) = 95.3 +/- 0.7%), the decrease in evoked force was exacerbated by 35% (P < 0.05) in response to further desaturation induced via Fi(O2) 0.17 (Sa(O2) = 87.8 +/- 0.5%) for the same duration and intensity of exercise. We conclude that the arterial O2 desaturation that occurs in fit subjects during high-intensity exercise in normoxia (-6 +/- 1% DeltaSa(O2) from rest) contributes significantly toward quadriceps muscle fatigue via a peripheral mechanism.     

Prolonged exercise to fatigue in humans impairs skeletal muscle Na+-K+-ATPase activity, sarcoplasmic reticulum Ca2+ release, and Ca2+ uptake.

Prolonged exhaustive submaximal exercise in humans induces marked metabolic changes, but little is known about effects on muscle Na+-K+-ATPase activity and sarcoplasmic reticulum Ca2+ regulation. We therefore investigated whether these processes were impaired during cycling exercise at 74.3 +/- 1.2% maximal O2 uptake (mean +/- SE) continued until fatigue in eight healthy subjects (maximal O2 uptake of 3.93 +/- 0.69 l/min). A vastus lateralis muscle biopsy was taken at rest, at 10 and 45 min of exercise, and at fatigue. Muscle was analyzed for in vitro Na+-K+-ATPase activity [maximal K+-stimulated 3-O-methylfluorescein phosphatase (3-O-MFPase) activity], Na+-K+-ATPase content ([3H]ouabain binding sites), sarcoplasmic reticulum Ca2+ release rate induced by 4 chloro-m-cresol, and Ca2+ uptake rate. Cycling time to fatigue was 72.18 +/- 6.46 min. Muscle 3-O-MFPase activity (nmol.min(-1).g protein(-1)) fell from rest by 6.6 +/- 2.1% at 10 min (P <0.05), by 10.7 +/- 2.3% at 45 min (P <0.01), and by 12.6 +/- 1.6% at fatigue (P <0.01), whereas 3[H]ouabain binding site content was unchanged. Ca2+ release (mmol.min(-1).g protein(-1)) declined from rest by 10.0 +/- 3.8% at 45 min (P <0.05) and by 17.9 +/- 4.1% at fatigue (P < 0.01), whereas Ca2+ uptake rate fell from rest by 23.8 +/- 12.2% at fatigue (P=0.05). However, the decline in muscle 3-O-MFPase activity, Ca2+ uptake, and Ca2+ release were variable and not significantly correlated with time to fatigue. Thus prolonged exhaustive exercise impaired each of the maximal in vitro Na+-K+-ATPase activity, Ca2+ release, and Ca2+ uptake rates. This suggests that acutely downregulated muscle Na+, K+, and Ca2+ transport processes may be important factors in fatigue during prolonged exercise in humans.     

Central and peripheral contributions to muscle fatigue in humans during sustained maximal effort

The purpose of this study was to estimate the relative contributions of central and peripheral factors to the development of human muscle fatigue. Nine healthy subjects [five male, four female; age = 30 (2) years, mean (SE)] sustained a maximum voluntary isometric contraction (MVC) of the ankle dorsiflexor muscles for 4 min. Fatigue was quantitated as the fall in MVC. Three measures of central activation and one measure of peripheral activation (compound muscle action potential, CMAP) were made using electromyography (EMG) and electrical stimulation. Measures of intramuscular metabolism were made using magnetic resonance spectroscopy. After exercise, MVC and electrically stimulated tetanic contraction (50 Hz, 500 ms) forces were 22.2 (3.7)% and 37.3 (7.1)% of pre-exercise values, respectively. The measures of central activation suggested some central fatigue during exercise: (1) the central activation ratio [MVC/(MVC + superimposed tetanic force)] fell from 0.94 (0.03) to 0.78 (0.09), (2) the MVC/tetanic force ratio fell from 2.3 (0.7) to 1.3 (0.7), and (3) the integral of the EMG (iEMG) signal decreased to 72.6 (9.1)% of the initial value, while the CMAP amplitude was unchanged. Intramuscular pH was associated by regression with the decline in MVC force (and therefore fatigue) and iEMG. The results indicate that central factors, which were not associated with altered peripheral excitability, contributed approximately 20% to the muscle fatigue developed, with the remainder being attributable to intramuscular (i.e., metabolic) factors. The association between pH and iEMG is consistent with proton concentration as a feedback mechanism for central motor drive during maximal effort.     

Impairment of Ca(2+) release in single Xenopus muscle fibers fatigued at varied extracellular PO(2).

We tested the hypothesis that the mechanisms involved in the more rapid onset of fatigue when O(2) availability is reduced in contracting skeletal muscle are similar to those when O(2) availability is more sufficient. Two series of experiments were performed in isolated, single skeletal muscle fibers from Xenopus laevis. First, relative force and free cytosolic Ca(2+) concentrations ([Ca(2+)](c)) were measured simultaneously in single fibers (n = 6) stimulated at increasing frequencies (0.25, 0.33, 0.5, and 1 Hz) at an extracellular PO(2) of either 22 or 159 Torr. Muscle fatigue (force = 50% of initial peak tension) occurred significantly sooner (P < 0.05) during the low- (237 +/- 40 s) vs. high-PO(2) treatments (280 +/- 38 s). Relative [Ca(2+)](c) was significantly decreased from maximal values at the fatigue time point during both the high- (72 +/- 4%) and low-PO(2) conditions (78 +/- 4%), but no significant difference was observed between the treatments. In the second series of experiments, using the same stimulation regime as the first, fibers (n = 6) exposed to 5 mM caffeine immediately after fatigue demonstrated an immediate but incomplete relative force recovery during both the low- (89 +/- 4%) and high-PO(2) treatments (82 +/- 3%), with no significant difference between treatments. Additionally, there was no significant difference in relative [Ca(2+)](c) between the high- (100 +/- 12% of prefatigue values) and low-PO(2) treatments (108 +/- 12%) on application of caffeine. These results suggest that in isolated, single skeletal muscle fibers, the earlier onset of fatigue that occurred during the low-extracellular PO(2) condition was modulated through similar pathways as the fatigue process during the high and involved a decrease in relative peak [Ca(2+)](c).     

Increased fatigue resistance of respiratory muscles during exercise after respiratory muscle endurance training

Respiratory muscle fatigue develops during exhaustive exercise and can limit exercise performance. Respiratory muscle training, in turn, can increase exercise performance. We investigated whether respiratory muscle endurance training (RMT) reduces exercise-induced inspiratory and expiratory muscle fatigue. Twenty-one healthy, male volunteers performed twenty 30-min sessions of either normocapnic hyperpnoea (n = 13) or sham training (CON, n = 8) over 4-5 wk. Before and after training, subjects performed a constant-load cycling test at 85% maximal power output to exhaustion (PRE(EXH), POST(EXH)). A further posttraining test was stopped at the pretraining duration (POST(ISO)) i.e., isotime. Before and after cycling, transdiaphragmatic pressure was measured during cervical magnetic stimulation to assess diaphragm contractility, and gastric pressure was measured during thoracic magnetic stimulation to assess abdominal muscle contractility. Overall, RMT did not reduce respiratory muscle fatigue. However, in subjects who developed >10% of diaphragm or abdominal muscle fatigue in PRE(EXH), fatigue was significantly reduced after RMT in POST(ISO) (inspiratory: -17 +/- 6% vs. -9 +/- 10%, P = 0.038, n = 9; abdominal: -19 +/- 10% vs. -11 +/- 11%, P = 0.038, n = 9), while sham training had no significant effect. Similarly, cycling endurance in POST(EXH) did not improve after RMT (P = 0.071), while a significant improvement was seen in the subgroup with >10% of diaphragm fatigue after PRE(EXH) (P = 0.017), but not in the sham training group (P = 0.674). However, changes in cycling endurance did not correlate with changes in respiratory muscle fatigue. In conclusion, RMT decreased the development of respiratory muscle fatigue during intensive exercise, but this change did not seem to improve cycling endurance.     

Fall in intracellular PO(2) at the onset of contractions in Xenopus single skeletal muscle fibers.

It remains uncertain whether the delayed onset of mitochondrial respiration on initiation of muscle contractions is related to O(2) availability. The purpose of this research was to measure the kinetics of the fall in intracellular PO(2) at the onset of a contractile work period in rested and previously worked single skeletal muscle fibers. Intact single skeletal muscle fibers (n = 11) from Xenopus laevis were dissected from the lumbrical muscle, injected with an O(2)-sensitive probe, mounted in a glass chamber, and perfused with Ringer solution (PO(2) = 32 +/- 4 Torr and pH = 7.0) at 20 degrees C. Intracellular PO(2) was measured in each fiber during a protocol consisting sequentially of 1-min rest; 3 min of tetanic contractions (1 contraction/2 s); 5-min rest; and, finally, a second 3-min contractile period identical to the first. Maximal force development and the fall in force (to 83 +/- 2 vs. 86 +/- 3% of maximal force development) in contractile periods 1 and 2, respectively, were not significantly different. The time delay (time before intracellular PO(2) began to decrease after the onset of contractions) was significantly greater (P < 0.01) in the first contractile period (13 +/- 3 s) compared with the second (5 +/- 2 s), as was the time to reach 50% of the contractile steady-state intracellular PO(2) (28 +/- 5 vs. 18 +/- 4 s, respectively). In Xenopus single skeletal muscle fibers, 1) the lengthy response time for the fall in intracellular PO(2) at the onset of contractions suggests that intracellular factors other than O(2) availability determine the on-kinetics of oxidative phosphorylation and 2) a prior contractile period results in more rapid on-kinetics.     

Muscle Na-K-pump and fatigue responses to progressive exercise in normoxia and hypoxia

To investigate the effects of hypoxia and incremental exercise on muscle contractility, membrane excitability, and maximal Na(+)-K(+)-ATPase activity, 10 untrained volunteers (age = 20 +/- 0.37 yr and weight = 80.0 +/- 3.54 kg; +/- SE) performed progressive cycle exercise to fatigue on two occasions: while breathing normal room air (Norm; Fi(O(2)) = 0.21) and while breathing a normobaric hypoxic gas mixture (Hypox; Fi(O(2)) = 0.14). Muscle samples extracted from the vastus lateralis before exercise and at fatigue were analyzed for maximal Na(+)-K(+)-ATPase (K(+)-stimulated 3-O-methylfluorescein phosphatase) activity in homogenates. A 32% reduction (P < 0.05) in Na(+)-K(+)-ATPase activity was observed (90.9 +/- 7.6 vs. 62.1 +/- 6.4 nmol.mg protein(-1).h(-1)) in Norm. At fatigue, the reductions in Hypox were not different (81 +/- 5.6 vs. 57.2 +/- 7.5 nmol.mg protein(-1).h(-1)) from Norm. Measurement of quadriceps neuromuscular function, assessed before and after exercise, indicated a generalized reduction (P < 0.05) in maximal voluntary contractile force (MVC) and in force elicited at all frequencies of stimulation (10, 20, 30, 50, and 100 Hz). In general, no differences were observed between Norm and Hypox. The properties of the compound action potential, amplitude, duration, and area, which represent the electromyographic response to a single, supramaximal stimulus, were not altered by exercise or oxygen condition when assessed both during and after the progressive cycle task. Progressive exercise, conducted in Hypox, results in an inhibition of Na(+)-K(+)-ATPase activity and reductions in MVC and force at different frequencies of stimulation; these results are not different from those observed with Norm. These changes occur in the absence of reductions in neuromuscular excitability.     

The effect of age and gender on the relative fatigability of the human adductor pollicis muscle

The purpose of this study was to examine the relative influence of such factors as age, gender, and absolute force on the fatiguability of the human adductor pollicis muscle. 12 young males (YM, 25.3 +/- 2.1 y), 12 young females (YF. 23.5 +/- 2.1 y), 12 older males (OM, 71.7 +/- 5.6 y) and 12 older females (OF, 69.5 +/- 4.6 y) participated. Three minutes of intermittent (5 s contraction, 2 s rest) maximal voluntary contractions (MVC) were used to fatigue the adductor pollicis muscle; the ulnar nerve was also stimulated in each 2 s rest period to evoke a maximal twitch. Males were stronger than females in both voluntary and evoked force (PT) in the young age group (MVC: YM, 10.0 +/- 2.7 kg vs. YF, 6.6 +/- 1.1 kg, P < 0.05) (PT: YM, 0.99 +/- 0.21 kg vs. YF, 0.71 +/- 0.12 kg, P < 0.05). In the older adults, however, males were stronger only in the evoked twitch (OM, 0.73 +/- 0.24 kg vs. OF, 0.48 +/- 0.07 kg, P < 0.05). There was no significant effect of gender or absolute muscle force on relative fatigability; the only variable found to significantly affect fatigability was age. Older adults were significantly less fatigable than young adults as indicated by the voluntary fatigue index (FI) (percentage of force reduction from baseline; FI-young, 40.2 +/- 12.6% vs. FI-old, 25.2 +/- 12.3%). This age effect, however, was more prominent in males than females (FI-YM, 44.7 +/- 10.5% vs. FI-OM, 24.2 +/- 10.7%, P < 0.01; FI-YF, 37.8 +/- 14.1% vs. FI-OF, 26.3 +/- 14.5%, P = 0.13). In conclusion, age was found to be the strongest single predictor of fatigability during short duration, intermittent exercise in human adductor pollicis muscle.     

Exercise-induced abdominal muscle fatigue in healthy humans.

The abdominal muscles have been shown to fatigue in response to voluntary isocapnic hyperpnea using direct nerve stimulation techniques. We investigated whether the abdominal muscles fatigue in response to dynamic lower limb exercise using such techniques. Eleven male subjects [peak oxygen uptake (VO2 peak) = 50.0 +/- 1.9 (SE) ml.kg(-1).min(-1)] cycled at >90% VO2 peak to exhaustion (14.2 +/- 4.2 min). Abdominal muscle function was assessed before and up to 30 min after exercise by measuring the changes in gastric pressure (Pga) after the nerve roots supplying the abdominal muscles were magnetically stimulated at 1-25 Hz. Immediately after exercise there was a decrease in Pga at all stimulation frequencies (mean -25 +/- 4%; P < 0.001) that persisted up to 30 min postexercise (-12 +/- 4%; P = 0.001). These reductions were unlikely due to changes in membrane excitability because amplitude, duration, and area of the rectus abdominis M wave were unaffected. Declines in the Pga response to maximal voluntary expiratory efforts occurred after exercise (158 +/- 13 before vs. 145 +/- 10 cmH2O after exercise; P = 0.005). Voluntary activation, assessed using twitch interpolation, did not change (67 +/- 6 before vs. 64 +/- 2% after exercise; P = 0.20), and electromyographic activity of the rectus abdominis and external oblique increased during these volitional maneuvers. These data provide new evidence that the abdominal muscles fatigue after sustained, high-intensity exercise and that the fatigue is primarily due to peripheral mechanisms.     

Inspiratory muscle work in acute hypoxia influences locomotor muscle fatigue and exercise performance of healthy humans

Our aim was to isolate the independent effects of 1) inspiratory muscle work (W(b)) and 2) arterial hypoxemia during heavy-intensity exercise in acute hypoxia on locomotor muscle fatigue. Eight cyclists exercised to exhaustion in hypoxia [inspired O(2) fraction (Fi(O(2))) = 0.15, arterial hemoglobin saturation (Sa(O(2))) = 81 +/- 1%; 8.6 +/- 0.5 min, 273 +/- 6 W; Hypoxia-control (Ctrl)] and at the same work rate and duration in normoxia (Sa(O(2)) = 95 +/- 1%; Normoxia-Ctrl). These trials were repeated, but with a 35-80% reduction in W(b) achieved via proportional assist ventilation (PAV). Quadriceps twitch force was assessed via magnetic femoral nerve stimulation before and 2 min after exercise. The isolated effects of W(b) in hypoxia on quadriceps fatigue, independent of reductions in Sa(O(2)), were revealed by comparing Hypoxia-Ctrl and Hypoxia-PAV at equal levels of Sa(O(2)) (P = 0.10). Immediately after hypoxic exercise potentiated twitch force of the quadriceps (Q(tw,pot)) decreased by 30 +/- 3% below preexercise baseline, and this reduction was attenuated by about one-third after PAV exercise (21 +/- 4%; P = 0.0007). This effect of W(b) on quadriceps fatigue occurred at exercise work rates during which, in normoxia, reducing W(b) had no significant effect on fatigue. The isolated effects of reduced Sa(O(2)) on quadriceps fatigue, independent of changes in W(b), were revealed by comparing Hypoxia-PAV and Normoxia-PAV at equal levels of W(b). Q(tw,pot) decreased by 15 +/- 2% below preexercise baseline after Normoxia-PAV, and this reduction was exacerbated by about one-third after Hypoxia-PAV (-22 +/- 3%; P = 0.034). We conclude that both arterial hypoxemia and W(b) contribute significantly to the rate of development of locomotor muscle fatigue during exercise in acute hypoxia; this occurs at work rates during which, in normoxia, W(b) has no effect on peripheral fatigue.     

Limitation of maximal O2 uptake and performance by acute hypoxia in dog muscle in situ

The factors that determine maximal O2 uptake (VO2max) and muscle performance during severe, acute hypoxemia were studied in isolated, in situ dog gastrocnemius muscle. Our hypothesis that VO2max is limited by O2 diffusion in muscle predicts that decreases in VO2max, caused by hypoxemia, will be accompanied by proportional decreases in muscle effluent venous PO2 (PvO2). By altering the fraction of inspired O2, four levels of arterial PO2 (PaO2) [21 +/- 2, 28 +/- 1, 44 +/- 1, and 80 +/- 2 (SE) Torr] were induced in each of eight dogs. Muscle arterial and venous circulation was isolated and arterial pressure held constant by pump perfusion. Each muscle worked maximally (3 min at 5-6 Hz, isometric twitches) at each PaO2. Arterial and venous samples were taken to measure lactate, [H+], PO2, PCO2, and muscle VO2. Muscle biopsies were taken to measure [H+] (homogenate method) and lactate. VO2max decreased with PaO2 and was linearly (R = 0.99) related to both PVO2 and O2 delivery. As PaO2 fell, fatigue increased while muscle lactate and [H+] increased. Lactate release from the muscle did not change with PaO2. This suggests a barrier to lactate efflux from muscle and a possible cause of the greater fatigue seen in hypoxemia. The gas exchange data are consistent with the hypothesis that VO2max is limited by peripheral tissue diffusion of O2.