Central basis of muscle fatigue in chronic fatigue syndrome.

We studied whether muscle fatigue, metabolism, or activation are abnormal in the chronic fatigue syndrome (CFS). Subjects performed both an intermittent submaximal and a sustained maximal voluntary isometric exercise protocol of the tibialis anterior muscle. The extent of fatigue, metabolic response, and changes in both M-wave amplitude and twitch tension during exercise were similar in patients and controls. The response to systemic exercise was also normal in the patients. However, voluntary activation of the tibialis was significantly lower in the patients during maximal sustained exercise. The results indicate that patients with CFS have (1) normal fatigability and metabolism at both the intracellular and systemic levels, (2) normal muscle membrane function and excitation-contraction coupling, and (3) an inability to fully activate skeletal muscle during intense, sustained exercise. This failure of activation was well in excess of that found in controls, suggesting an important central component of muscle fatigue in CFS.

Physiology of fatigue in amyotrophic lateral sclerosis.

We investigated the mechanisms of muscle fatigue in ALS. In the muscles of ALS patients and healthy control subjects, we examined (1) fatigue using measurements of muscle force, (2) energy metabolism using phosphorus-31 magnetic resonance spectroscopy, and (3) activation using neurophysiologic measures and MRI. During 25 minutes of intermittent isometric exercise of the tibialis anterior muscle, both maximum voluntary and tetanic force declined more in patients than in controls, indicating greater fatigability in ALS. There was a similar decline of voluntary and tetanic force, suggesting that much of the fatigue was not central. Evoked compound muscle action potential amplitudes were preserved during exercise in both groups, indicating no failure of neuromuscular transmission; this result suggests that the source of fatigue was not at the neuromuscular junction or within the muscle membrane. In spite of greater fatigability, changes during exercise in energy metabolites and proton signal intensity tended to be less in ALS patients compared with controls, suggesting impaired muscular activation. We conclude that the greater muscle fatigue in ALS patients results from activation impairment, due in part to alterations distal to the muscle membrane.

Slowed muscle contractile properties are not associated with a decreased EMG/force relationship in older humans.

We tested the hypothesis that, as a result of slower muscle contractile properties, the electromyogram (EMG)/force relationship is decreased during voluntary contractions in older compared to young humans. We studied 22 young (32 +/- 1 yr, mean +/- SE) and 20 older (72 +/- 1) men and women. To quantitate ankle dorsiflexor muscle properties, we measured isometric twitch time to peak force and maximal relaxation rate, the rates of tetanic (50 Hz, 1 s) force development and relaxation, and the stimulated force-frequency relationship. The voluntary EMG/force relationship was determined during isometric dorsflexion from 10% to 100% MVC (maximal voluntary isometric contraction force) in 10% MVC increments. Twitch time to peak force and the rates of tetanic force development and relaxation were slower in the older subjects. Greater relative force was produced in older compared to young adults at 10 Hz. During voluntary contractions, EMG was greater in older compared to young subjects at lower intensities (10% and 20% MVC). Thus, although the older adults exhibited a slowing of contractile properties and summation of force when stimulated at 10 Hz, the voluntary EMG/force relationship was increased rather than decreased at low contraction intensities, compared to young adults. We conclude that the slowing of contractile properties does not result in increased neural "efficiency" of voluntary force production in older adults. This novel observation may have important functional relevance to the performance of activities of daily living, particularly in a more frail older population.

Skeletal muscle oxidative capacity in young and older women and men.

It has been suggested that a decline in skeletal muscle oxidative capacity is a general consequence of aging in humans. However, previous studies have not always controlled for the effects of varying levels of physical activity on muscle oxidative capacity. To test the hypothesis that, when matched for comparable habitual physical activity levels, there would be no age-related decline in the oxidative capacity of a locomotor muscle, the postexercise recovery time of phosphocreatine was compared in the tibialis anterior muscle of young [n = 19; 33.8 +/- 4.8 (SD) yr] and older [n = 18; 75.5 +/- 4.5 yr] healthy women and men of similar, relatively low, activity levels. The intramuscular metabolic measurements were accomplished by using phosphorus magnetic resonance spectroscopy. The results indicate that there was no age effect on the postexercise recovery time of phosphocreatine recovery, thus supporting the stated hypothesis. These data suggest that there is no requisite decline in skeletal muscle oxidative capacity with aging in humans, at least through the seventh decade.

Specific strength and voluntary muscle activation in young and elderly women and men.

The extents to which decreased muscle size or activation are responsible for the decrease in strength commonly observed with aging remain unclear. Our purpose was to compare muscle isometric strength [maximum voluntary contraction (MVC)], cross-sectional area (CSA), specific strength (MVC/CSA), and voluntary activation in the ankle dorsiflexor muscles of 24 young (32 +/- 1 yr) and 24 elderly (72 +/- 1 yr) healthy men and women of similar physical activity level. Three measures of voluntary muscle activation were used: the central activation ratio [MVC/(MVC + superimposed force)], the maximal rate of voluntary isometric force development, and foot tap speed. Men had higher MVC and CSA than did women. Young men had higher MVC compared with elderly men [262 +/- 19 (SE) vs. 197 +/- 22 N, respectively], whereas MVC was similar in young and elderly women (136 +/- 15 vs. 149 +/- 16 N, respectively). CSA was greater in young compared with elderly subjects. There was no age-related impairment of specific strength, central activation ratio, or the rate of voluntary force development. Foot tap speed was reduced in elderly (34 +/- 1 taps/10 s) compared with young subjects (47 +/- 1 taps/10 s). These results suggest that isometric specific strength and the ability to fully and rapidly activate the dorsiflexor muscles during a single isometric contraction were unimpaired by aging. However, there was an age-related deficit in the ability to perform rapid repetitive dynamic contractions.

Phases of metabolism during progressive exercise to fatigue in human skeletal muscle.

The purpose of this study was to assess noninvasively both the "oxidative potential" and the sequence of metabolic events that occur during the transition from rest to fatigue in an isometrically exercising muscle. 31P-magnetic resonance spectroscopy was used to obtain continuous measures of intracellular phosphocreatine (PCr), inorganic phosphate (Pi), and proton concentration ([H+]) in the tibialis anterior muscle of eight healthy human volunteers during a progressive isometric exercise protocol. The exercise protocol consisted of 2-min stages, with a duty cycle consisting of 4 s of contraction and 6 s of relaxation, beginning at 10% of the force from an initial maximal voluntary contraction (MVC) and increasing by 10% to a final load of 80% MVC. An MVC was performed at the beginning of each stage; a decrease in MVC indicated fatigue. The initial linear slope of the relationship between force and Pi/PCr was used as an index of oxidative potential for the muscle. This initial slope ranged from 85 to 167% MVC/(Pi/PCr), indicating substantial variability of oxidative potential in these subjects. The changes in Pi/PCr and [H+] over time were best described with a bilinear fit of the individual data. The inflection point for each fit was defined as the point at which the slopes intersected. The Pi/PCr inflection point occurred at a similar value of Pi/PCr in all subjects [0.47 +/- 0.04 (SE)]. The Pi/PCr inflection point occurred significantly earlier (7.8 +/- 0.7 min) than the [H+] inflection point (9.3 +/- 0.4 min, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Skeletal muscle contractile and noncontractile components in young and older women and men.

To examine the influences of age, gender, and habitual physical activity level on human skeletal muscle composition, we developed a relatively simple magnetic resonance imaging method for the quantitation of leg anterior compartment contractile and noncontractile content. We studied 23 young (11 women and 12 men, 26-44 yr old) and 21 older (10 women and 11 men, 65-83 yr old) healthy adults. Analysis was by two-factor (age, gender) ANOVA. Physical activity, quantitated by three-dimensional accelerometer worn about the waist for 1 wk, was not different between groups. Men had larger contractile and noncontractile cross-sectional areas (cm(2)) than women, with no gender effect on percent noncontractile area. Young subjects had larger contractile areas and smaller absolute (cm(2)) and relative (percent total) noncontractile areas than older subjects. There was a significant linear relationship between physical activity and percent noncontractile area in older (r = -0.68, P = 0.002) but not young subjects. These data demonstrate a more than twofold increase in the noncontractile content of locomotor muscles in older adults and provide novel support for physical activity as a modulator of this age-related change in muscle composition.

Metabolic effects of training in humans: a 31P-MRS study.

The purpose of this study was to determine the feasibility of measuring with 31P nuclear magnetic resonance the effects of an endurance training program on the high-energy phosphate metabolism of exercising human skeletal muscle. The system used included a 1.9-T 30-cm-bore Oxford Systems superconducting magnet, a PhosphoEnergetics spectrometer, and a modified Cybex isokinetic ergometer. Seven healthy human volunteers exercised their wrist flexor muscles 20 min/day 5 days/wk for 8 wk. Testing before and after the training period consisted of a performance test to measure muscle functional capacity and a ramp test to measure the work-energy cost relationship of the exercising muscles. The results indicate that the subjects had a significant increase in their work output on the 10-min performance test after training. They also exhibited an increase in the work-energy cost relationship on the ramp test as indicated by a decrease in peak Pi-to-phosphocreatine ratio and an increase in pH at the same relative power output after training. These results indicate that 1) the training program was sufficient to elicit a training effect and 2) this effect was observed with 31P nuclear magnetic resonance as an increased potential for oxidative metabolism, particularly at the high exercise levels.

MRI measures of perfusion-related changes in human skeletal muscle during progressive contractions.

Although skeletal muscle perfusion is fundamental to proper muscle function, in vivo measurements are typically limited to those of limb or arterial blood flow, rather than flow within the muscle bed itself. We present a noninvasive functional MRI (fMRI) technique for measuring perfusion-related signal intensity (SI) changes in human skeletal muscle during and after contractions and demonstrate its application to the question of occlusion during a range of contraction intensities. Eight healthy men (aged 20-31 yr) performed a series of isometric ankle dorsiflexor contractions from 10 to 100% maximal voluntary contraction. Axial gradient-echo echo-planar images (repetition time = 500 ms, echo time = 18.6 ms) were acquired continuously before, during, and following each 10-s contraction, with 4.5-min rest between contractions. Average SI in the dorsiflexor muscles was calculated for all 240 images in each contraction series. Postcontraction hyperemia for each force level was determined as peak change in SI after contraction, which was then scaled to that obtained following a 5-min cuff occlusion of the thigh (i.e., maximal hyperemia). A subset of subjects (n = 4) performed parallel studies using venous occlusion plethysmography to measure limb blood flow. Hyperemia measured by fMRI and plethysmography demonstrated good agreement. Postcontraction hyperemia measured by fMRI scaled with contraction intensity up to approximately 60% maximal voluntary contraction. fMRI provides a noninvasive means of quantifying perfusion-related changes during and following skeletal muscle contractions in humans. Temporal changes in perfusion can be observed, as can the heterogeneity of perfusion across the muscle bed.

Blunted pressor and intramuscular metabolic responses to voluntary isometric exercise in multiple sclerosis.

To test the hypothesis that a lower mean arterial pressure (MAP) response during voluntary isometric exercise in multiple sclerosis (MS) is related to a dampened muscle metabolic signal, 9 MS and 11 control subjects performed an isometric dorsiflexor contraction at 30% maximal voluntary contraction until target failure (endurance time). We made continuous and noninvasive measurements of heart rate and MAP (Finapres) and of intramuscular pH and P(i) (phosphorus magnetic resonance spectroscopy) in a subset of 6 MS and 10 control subjects. Endurance times and change in heart rate were similar in MS and control subjects. The decrease in pH and increase in P(i) were less throughout exercise in MS compared with control subjects, as was the change in MAP response. Differences in muscle strength accounted for some of the difference in MAP response between groups. Cardiovascular responses during Valsalva and cold pressor tests were similar in MS and control subjects, suggesting that the blunted MAP response during exercise in MS was not due to a generalized dysautonomia. The dampened metabolic response in MS subjects was not explained by inadequate central muscle activation. These data suggest that the blunted pressor response to exercise in MS subjects may be largely appropriate to a blunted muscle metabolic response and differences in contracting muscle mass.

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.

Effects of age on human muscle torque, velocity, and power in two muscle groups.

The purpose of this study was to test the hypotheses that, under isovelocity conditions, older compared with young humans would 1). be slower to reach target velocity and 2). exhibit a downward shift in the torque-velocity and power-velocity relationships in the ankle dorsiflexor and knee extensor muscles. We studied 12 young (26 +/- 5 yr, 6 men/6 women) and 12 older (72 +/- 6 yr, 6 men/6 women) healthy adults during maximal voluntary concentric contractions at preset target velocities (dorsiflexion: 0-240 degrees /s; knee extension: 0-400 degrees /s) using an isokinetic dynamometer. The time to target velocity was longer in older subjects in the dorsiflexors and knee extensors (both P

Strength, skeletal muscle composition, and enzyme activity in multiple sclerosis.

This study examined functional, biochemical, and morphological characteristics of skeletal muscle in nine multiple sclerosis (MS) patients and eight healthy controls in an effort to ascertain whether intramuscular adaptations could account for excessive fatigue in this disease. Analyses of biopsies of the tibialis anterior muscle showed that there were fewer type I fibers (66 +/- 6 vs. 76 +/- 6%), and that fibers of all types were smaller (average downward arrow26%) and had lower succinic dehydrogenase (SDH; average downward arrow40%) and SDH/alpha-glycerol-phosphate dehydrogenase (GPDH) but not GPDH activities in MS vs. control subjects, suggesting that muscle in this disease is smaller and relies more on anaerobic than aerobic-oxidative energy supply than does muscle of healthy individuals. Maximal voluntary isometric force for dorsiflexion was associated with both average fiber cross-sectional area (r = 0.71, P = 0.005) and muscle fat-free cross-sectional area by magnetic resonance imaging (r = 0.80, P < 0. 001). Physical activity, assessed by accelerometer, was associated with average fiber SDH/GPDH (r = 0.78, P = 0.008). There was a tendency for symptomatic fatigue to be inversely associated with average fiber SDH activity (r = -0.57, P = 0.068). The results of this study suggest that the inherent characteristics of skeletal muscle fibers per se and of skeletal muscle as a whole are altered in the direction of disuse in MS. They also suggest that changes in skeletal muscle in MS may significantly affect function.

Magnetic resonance spectroscopy studies of human muscle.

The use of MRS has become more widespread as cost and availability have improved. It has been demonstrated that MRS of human skeletal muscle can play a significant role in (1) understanding healthy muscle metabolism and the mechanisms of muscle fatigue, (2) understanding the effects of disease on muscle metabolism and function, (3) monitoring the efficacy of therapeutic intervention, and (4) the confirmation of disease diagnoses. The results of the 31P MRS studies of disease are summarized in the Table 1. A few conditions (McArdle's, PFK deficiency) are associated with failure to develop acidosis during exercise. This response appears to be relatively specific to these metabolic myopathies. For most of the conditions reviewed here, however, the metabolic findings of reduced PCr/Pi and greater acidosis during exercise with impaired recovery of PCr/Pi and pH are very similar. The nonspecificity of the MRS results suggests the possibility that a common mechanism may be at work in all of these diseases. A major question to arise from clinical studies using MRS concerns the extent to which deconditioning may have played a role in some of these findings. This is because conditions associated with muscle weakness, rapid fatiguability, and muscle pain during or following vigorous physical activity may also be those that lead to deconditioning. In virtually all studies reviewed here, healthy, active subjects were used as controls. There are no examples in which controls were appropriately matched to the subjects for their level of conditioning. Conditioning could be assessed by questionnaire, activity logs, activity monitoring devices, or measurements of conditioning effects such as maximal oxygen consumption. The role of deconditioning in the decreased quality of life of persons with chronic diseases has not been fully explored. Future studies of chronic disease using MRS should combine MRS with other techniques to further probe the mechanisms of muscle metabolism under various conditions, and the extent to which these mechanisms are sensitive to the level of physical conditioning.

Quantitation of lower physical activity in persons with multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that often affects the motor system. We tested the hypothesis that physical activity was lower in a group of 17 MS patients (mean +/- SD; age = 46 +/- 6 yr, 11 females, 6 males) compared with 15 healthy sedentary control subjects (age = 44 +/- 7 yr, 9 females, 6 males). Physical activity was measured with a three-dimensional accelerometer and with an activity questionnaire for 7 d. Vector magnitude values from the accelerometer for the MS and sedentary control subjects were 121,027 +/- 59,336 and 185,892 +/- 60,566 arbitrary units/day, respectively (P = 0.01). Estimated energy expenditure values derived from the questionnaire were 35.9 +/- 3.0 and 36.2 +/- 4.1 Kcal.kg-1.d-1 (NS), respectively. Thus, when measured directly with an accelerometer, activity was lower in MS compared with sedentary control subjects. The data also suggest that the accelerometer was more sensitive than the questionnaire for detecting differences in activity between two relatively sedentary populations, including one with neurologic disease.

Mechanisms of human muscle fatigue. Quantitating the contribution of metabolic factors and activation impairment.

Both metabolic factors and impairment of activation appear to play a role in human muscle fatigue. By measuring force, EMG and metabolites during fatiguing exercise and recovery, we are attempting to estimate the contribution of the different factors which produce fatigue.

Postural control in women with multiple sclerosis: effects of task, vision and symptomatic fatigue.

People with multiple sclerosis (MS) often report problems with balance, which may be most apparent during challenging postural tasks such as leaning or reaching, and when relying on non-visual sensory systems. An additional obstacle facing people with MS is a high incidence of symptomatic fatigue (>70%). The purpose of this study was to investigate the changes in balance during upright stance in individuals with mild-to-moderate disability due to MS under normal and restricted vision and different levels of self-reported fatigue. Limb loading asymmetry, sway and magnitude of postural shift in center of pressure, and time-to-contact the stability boundary of the center of mass and center of pressure were assessed during quiet standing and maximal lean and reach tasks. Compared to controls, people with MS displayed greater postural sway, greater loading asymmetry, and shorter time-to-contact during quiet standing. In the postural perturbation tasks the MS group had smaller postural shifts and reduced stability compared to controls in the direction perpendicular to the lean and reach. Limiting vision increased loading asymmetry during quiet standing and postural instability during backward lean in the MS group. Inducing additional fatigue in the MS group did affect postural control in the more challenging balance conditions but had no impact during quiet upright standing. The results of this study indicate subtle changes in postural control during standing in people with mild-to-moderate impairments due to MS.

Blood flow does not limit skeletal muscle force production during incremental isometric contractions.

It has been suggested that a transient limitation in blood flow during intermittent muscular contractions can contribute to muscle fatigue, and that this limitation is greater as contraction intensity increases. We investigated skeletal muscle blood flow and fatigue in 13 healthy, untrained men (21-27 years) during 16 min of intermittent (4 s contract, 6 s relax) isometric dorsiflexor contractions. Contractions began at 10% of pre-exercise maximal voluntary contraction (MVC) force and increased by 10% every 2 min. Hyperemia (i.e., post-contraction blood flow, measured by venous occlusion plethysmography) and MVC were measured at the end of each stage. Muscle volume measures were obtained using magnetic resonance imaging. After 10 min of exercise, submaximal force and post-contraction hyperemia plateaued. MVC fell from 8 min of exercise onwards (p=0.004), and this onset of fatigue preceded the plateau in submaximal force and hyperemia. Despite a large range in dorsiflexor muscle size (66.3-176.4 cm(3)) and strength (112.5-421.8 N), neither muscle size nor strength were related to fatigue. The temporal dissociation between changes in blood flow and the onset of fatigue (fall of MVC) suggest that limited blood flow was not a factor in the impaired force production observed during intermittent isometric dorsiflexor contractions in healthy young men. Additionally, post-contraction hyperemia increased linearly with increasing contraction intensity, reflecting a match between blood flow and force production throughout the protocol that was independent of fatigue.

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.