Peptide toxin blockers of voltage-sensitive K+ channels: inotropic effects on diaphragm.

Agents that block many types of K+ channels (e.g., the aminopyridines) have substantial inotropic effects in skeletal muscle. Specific blockers of ATP-sensitive and Ca2+-activated K+ channels, on the other hand, do not, or minimally, alter the force of nonfatigued muscle, consistent with a predominant role for voltage-gated K+ channels in regulating muscle force. To test this more directly, we examined the effects of peptide toxins, which in other tissues specifically block voltage-gated K+ channels, on rat diaphragm in vitro. Twitch force was increased in response to alpha-, beta-, and gamma-dendrotoxin and tityustoxin Kalpha (17 +/- 6, 22 +/- 5, 42 +/- 14, and 13 +/- 5%; P < 0.05, < 0.01, < 0.05, < 0.05, respectively) but not in response to delta-dendrotoxin or BSA (in which toxins were dissolved). Force during 20-Hz stimulation was also increased significantly by alpha-, beta-, and gamma-dendrotoxin and tityustoxin Kalpha. Among agents, increases in twitch force correlated with the degree to which contraction time was prolonged (r = 0.88, P < 0.02). To determine whether inotropic effects could be maintained during repeated contractions, muscle strips underwent intermittent 20-Hz train stimulation for a duration of 2 min in presence or absence of gamma-dendrotoxin. Force was significantly greater with than without gamma-dendrotoxin during repetitive stimulation for the first 60 s of repetitive contractions. Despite the approximately 55% higher value for initial force in the presence vs. absence of gamma-dendrotoxin, the rate at which fatigue occurred was not accelerated by the toxin, as assessed by the amount of time over which force declined by 25 and 50%. These data suggest that blocking voltage-activated K+ channels may be a useful therapeutic strategy for augmenting diaphragm force, provided less toxic blockers of these channels can be found.     

Gas exchange during separate diaphragm and intercostal muscle breathing.

In patients with diaphragm paralysis, ventilation to the basal lung zones is reduced, whereas in patients with paralysis of the rib cage muscles, ventilation to the upper lung zones in reduced. Inspiration produced by either rib cage muscle or diaphragm contraction alone, therefore, may result in mismatching of ventilation and perfusion and in gas-exchange impairment. To test this hypothesis, we assessed gas exchange in 11 anesthetized dogs during ventilation produced by either diaphragm or intercostal muscle contraction alone. Diaphragm activation was achieved by phrenic nerve stimulation. Intercostal muscle activation was accomplished by electrical stimulation by using electrodes positioned epidurally at the T(2) spinal cord level. Stimulation parameters were adjusted to provide a constant tidal volume and inspiratory flow rate. During diaphragm (D) and intercostal muscle breathing (IC), mean arterial Po(2) was 97.1 +/- 2.1 and 88.1 +/- 2.7 Torr, respectively (P < 0.01). Arterial Pco(2) was lower during D than during IC (32.6 +/- 1.4 and 36.6 +/- 1.8 Torr, respectively; P < 0.05). During IC, oxygen consumption was also higher than that during D (0.13 +/- 0.01 and 0.09 +/- 0.01 l/min, respectively; P < 0.05). The alveolar-arterial oxygen difference was 11.3 +/- 1.9 and 7.7 +/- 1.0 Torr (P < 0.01) during IC and D, respectively. These results indicate that diaphragm breathing is significantly more efficient than intercostal muscle breathing. However, despite marked differences in the pattern of inspiratory muscle contraction, the distribution of ventilation remains well matched to pulmonary perfusion resulting in preservation of normal gas exchange.     

Severe muscle dysfunction precedes collagen tissue proliferation in mdx mouse diaphragm.

After extensive necrosis, progressive diaphragm muscle weakness in the mdx mouse is thought to reflect progressive replacement of contractile tissue by fibrosis. However, little has been documented on diaphragm muscle performance at the stage at which necrosis and fibrosis are limited. Diaphragm morphometric characteristics, muscle performance, and cross-bridge (CB) properties were investigated in 6-wk-old control (C) and mdx mice. Compared with C, maximum tetanic tension and shortening velocity were 37 and 32% lower, respectively, in mdx mice (each P < 0.05). The total number of active CB per millimeter squared (13.0 +/- 1.2 vs. 18.4 +/- 1.7 x 10(9)/mm(2), P < 0.05) and the CB elementary force (8.0 +/- 0.2 vs. 9.0 +/- 0.1 pN, P < 0.01) were lower in mdx than in C. The time cycle duration was lower in mdx than in C (127 +/- 18 vs. 267 +/- 61 ms, P < 0.05). Percentages of fiber necrosis represented 2.8 +/- 0.6% of the total muscle fibers, and collagen surface area occupied 3.6 +/- 0.7% in mdx diaphragm. Our results pointed to severe muscular dysfunction in mdx mouse diaphragm, despite limited necrotic and fibrotic lesions.     

Effects of hypoxia and hypercapnia on geniohyoid contractility and endurance

Sleep apnea and other respiratory diseases produce hypoxemia and hypercapnia, factors that adversely affect skeletal muscle performance. To examine the effects of these chemical alterations on force production by an upper airway dilator muscle, the contractile and endurance characteristics of the geniohyoid muscle were examined in situ during severe hypoxia (arterial PO2 less than 40 Torr), mild hypoxia (PO2 45-65 Torr), and hypercapnia (PCO2 55-80 Torr) and compared with hyperoxic-normocapnic conditions in anesthetized cats. Muscles were studied at optimal length, and contractile force was assessed in response to supramaximal electrical stimulation of the hypoglossal nerve (n = 7 cats) or geniohyoid muscle (n = 2 cats). There were no significant changes in the twitch kinetics or force-frequency curve of the geniohyoid muscle during hypoxia or hypercapnia. However, the endurance of the geniohyoid, as reflected in the fatigue index (ratio of force at 2 min to initial force in response to 40-Hz stimulation at a duty cycle 0.33), was significantly reduced by severe hypoxia but not by hypercapnia or mild hypoxia. In addition, the downward shift in the force-frequency curve after the repetitive stimulation protocol was greater during hypoxia than hyperoxia, especially at higher frequencies. In conclusion, the ability of the geniohyoid muscle to maintain force output during high levels of activation is adversely affected by severe hypoxia but not mild hypoxia or hypercapnia. However, none of these chemical perturbations affected muscle contractility acutely.     

Effects of chronic nicotine exposure on electrogenic activity of the Na+, K(+)-ATPase and contractility in the rat diaphragm muscle

Rats were chronically treated with nicotine via subcutaneous injections up to a dose 6 mg/kg/day during 2-3 weeks. After this period, resting membrane potential and action potentials of muscle fibres as well as isometric twitch and tetanic (20 s(-1) and 50(-1)) contractions of isolated rat diaphragm were studied. To estimate electrogenic contribution of the alpha2 isoform of the Na+, K(+)-ATPase ouabain in concentration 1 microM was used. Chronic nicotine exposure induced depolarization of resting membrane potential of 2.2 +/- 0.6 mV (p < 0.01). In rats chronically exposed to nicotine, electrogenic contribution of the Na+, K(+)-ATPase alpha2 isoform was twofold lesser than in control animals (3.7 +/- 0.6 mV and 6.4 +/- 0.6 mV, respectively, p < 0.01). Chronic nicotine exposure did not affect force of twitch and tetanic contractions in response to direct or indirect stimulation. A decrease in the twitch contraction time as well as in the rise time of tetanic contractions was observed. Fatigue dynamics was unchanged. The results suggest that chronic nicotine exposure leads to decrease of the Na+, K(+)-ATPase alpha2 isoform electrogenic activity, and as a consequence to damage of the rat diaphragm muscle electogenesis.     

Contractile and endurance properties of geniohyoid and diaphragm muscles

Despite the wealth of information about the neural control of pharyngeal dilator muscles, little is known about their intrinsic physiological properties. In the present study the in situ isometric contractility and endurance of a pharyngeal dilator, the geniohyoid muscle, were compared with properties of the diaphragm in 12 anesthetized artificially ventilated cats. The contraction time (means +/- SE) of the geniohyoid (27 +/- 2 ms) was shorter than that of the diaphragm (36 +/- 3 ms; P less than 0.0005), as was the half-relaxation time (29 +/- 2 vs. 45 +/- 4 ms; P less than 0.002). The faster contraction and relaxation of the geniohyoid compared with the diaphragm were appropriately reflected in the shape of the force-frequency curves for the two muscles, with that of the geniohyoid located to the right of the diaphragm force-frequency curve. The endurance properties of the two muscles were assessed using repetitive stimulation at 40 Hz in trains lasting 0.33 s, with one train repeated every second. The ratio of force at the end of 2 min of repetitive stimulation to initial force was 0.67 +/- 0.06 for the geniohyoid and 0.15 +/- 0.03 for the diaphragm (P less than 0.00001). After the repetitive stimulation, the muscle force generated in response to a range of stimulus frequencies was reduced to a greater extent for the diaphragm than for the geniohyoid muscle. These results indicate that the geniohyoid muscle has a faster physiological profile than does the diaphragm yet is relatively resistant to fatigue when driven at high rates.     

Fatigue from high- and low-frequency muscle stimulation: contractile and biochemical alterations

This study examined the effect of high- (75 Hz, 1 min) and low- (5 Hz, 1.5 min) frequency stimulation on contractile and biochemical properties of the diaphragm. Tension was reduced to 21 +/- 1 and 54 +/- 2% (SE) of the initial value after high- and low-frequency stimulation, respectively. After 0, 0.25, 1, and 2 min of recovery from high-frequency stimulation, 5 Hz elicited more force (expressed as % of initial tension) than 75-Hz stimulation. Time 0 recovery values were 21 +/- 1 and 78 +/- 6% of the initial force for 75- and 5-Hz stimulation, respectively. By 1 min of recovery, force elicited by 5-Hz stimulation had returned to the prefatigue value. In contrast, force production with 75-Hz stimulation did not full recover until 10-15 min. After fatigue produced by low-frequency stimulation, force production with 5-Hz stimulation was reduced to 54 +/- 2% of the initial tension, a value significantly lower than the 71 +/- 2% of initial force elicited by 75-Hz stimulation. Force production with 5-Hz stimulation increased rapidly in the first 15 s of recovery (54 +/- 2% at 0 and 70 +/- 2% at 15 s) and by 5 min was significantly greater than the force elicited by 75-Hz stimulation (100 +/- 3 vs. 93 +/- 1%). As before, force production at 75-Hz stimulation did not fully recover until 10-15 min. Both fatigue protocols produced a significant prolongation in isometric twitch contraction and one-half relaxation times. Creatine phosphate (CP) concentration was reduced and muscle lactate increased by both fatigue protocols.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Increased fatigue of isovelocity vs. isometric contractions of canine diaphragm

A comparison of fatigue as a loss of force with repeated contractions over time was performed in canine respiratory muscle by isometric (nonshortening) and isovelocity (shortening) contractions. In situ diaphragm muscle strips were attached to a linear ergometer and electrically stimulated (30 or 40 Hz) via the left phrenic nerve to produce either isometric (n = 12) or isovelocity (n = 12) contractions (1.5 s) from optimal muscle length (Lo = 8.8 cm). Similar velocities of shortening between isovelocity experiments [0.19 +/- 0.02 (SD) Lo/S] were produced by maximizing the mean power output (Wmax = 210 +/- 27 mW/cm2) that could be developed over 1.5 s when displacement was approximately 0.30 Lo. Initial peak isometric tension was 1.98 kg/cm2, whereas initial peak isovelocity tension was 1.84 kg/mc2 (P less than 0.01) or 93% of initial isometric tension. Fatigue trials of 5 min were conducted on muscles contracting at a constant duty cycle (0.43). At the end of the trials, peak isovelocity tension had fallen to 50% of initial isometric tension (P less than 0.01), whereas peak isometric tension had only fallen by 27%. These results indicate that muscle shortening during force production has a significant influence on diaphragm muscle fatigue. We conclude that the effects of shortening on fatigue must be considered in models of respiratory muscle function, because these muscles typically shorten during breathing.     

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.     

Apocynin improves diaphragmatic function after endotoxin administration.

Free radicals are known to play an important role in modulating the development of respiratory muscle dysfunction during sepsis. Moreover, neutrophil numbers increase in the diaphragm after endotoxin administration. Whether or not superoxide derived from infiltrating white blood cells contributes to muscle dysfunction during sepsis is, however, unknown. The purpose of the present study was to examine the effect of apocynin, an inhibitor of the superoxide-generating neutrophil NADPH complex, on endotoxin-induced diaphragmatic dysfunction. We studied groups of rats given saline, endotoxin, apocynin, or both endotoxin and apocynin. Animals were killed 18 h after injection, a portion of the diaphragm was used to assess force generation, and the remaining diaphragm was used for determination of 4-hydroxynonenal (a marker of lipid peroxidation) and nitrotyrosine levels (a marker of free radical-mediated protein modification). We found that endotoxin reduced diaphragm force generation and that apocynin partially prevented this decrease [e.g., force in response to 20 Hz was 23 +/- 1 (SE), 12 +/- 2, 23 +/- 1, and 19 +/- 1 N/cm(2), respectively, for saline, endotoxin, apocynin, and endotoxin/apocynin groups; P < 0.001]. Apocynin also prevented endotoxin-mediated increases in diaphragm 4-hydroxynonenal and nitrotyrosine levels (P < 0.01). These data suggest that neutrophil-derived free radicals contribute to diaphragmatic dysfunction during sepsis.     

Muscle contractility in chronic disorders of neuromuscular transmission

Muscle contractility of the thumb was studied in 24 normal subjects, 84 patients with myasthenia and 4 patients with hypothyrosis in response to supramaximal stimulation, on the basis of the time of contraction and semi-relaxation, staircase phenomena, and posttetanic potentiation. During hormonal therapy, the patients with myasthenia and those with hypothyrosis treated by substitution therapy manifested the normalization of the staircase and posttetanic potentiation, reduction of the contraction force and twitch time during single contraction. The comparison of the changes seen in the contraction force, staircase and posttetanic potentiation during examination of the patients over time suggested that the muscle has a regulatory system that determines the force and twitch time of muscle contraction.     

Abnormal neurovascular control during exercise is linked to heart failure severity

The purpose of this study was to determine if abnormalities of sympathetic neural and vascular control are present in mild and/or severe heart failure (HF) and to determine the underlying afferent mechanisms. Patients with severe HF, mild HF, and age-matched controls were studied. Muscle sympathetic nerve activity (MSNA) and forearm vascular resistance (FVR) in the nonexercising arm were measured during mild and moderate static handgrip. MSNA during moderate handgrip was higher at baseline and throughout exercise in severe HF vs. mild HF (peak MSNA 67 +/- 3 vs. 54 +/- 3 bursts/min, P < 0.0001) and higher in mild HF vs. controls (33 +/- 3 bursts/min, P < 0.0001), but the change in MSNA was not different between the groups. The change in FVR was not significantly different between the three groups during static exercise. During isolation of muscle metaboreceptors, MSNA and blood pressure remained elevated in normal controls and mild HF but not in severe HF. During mild handgrip, the increase in MSNA was exaggerated in severe HF vs. controls and mild HF, in whom MSNA did not increase. In summary, the increase in MSNA during static exercise in severe HF appears to be attributable to exaggerated central command or muscle mechanoreceptor control, not muscle metaboreceptor control.     

Effects of DAP on diaphragm force and fatigue, including fatigue due to neurotransmission failure

Van Lunteren, Erik, and Michelle Moyer. Effects of DAPon diaphragm force and fatigue, including fatigue due toneurotransmission failure. J. Appl.Physiol. 81(5): 2214-2220, 1996.Among theaminopyridines, 3,4-diaminopyridine (DAP) is a more effectiveK⁺ channel blocker than is4-aminopyridine (4-AP), and, furthermore, DAP enhances neuromusculartransmission. Because 4-AP improves muscle contractility, wehypothesized that DAP would also increase force and, in addition,ameliorate fatigue and improve the neurotransmission failure componentof fatigue. Rat diaphragm strips were studied in vitro (37°C). Infield-stimulated muscle, 0.3 mM DAP significantly increased diaphragmtwitch force, prolonged contraction time, and shifted theforce-frequency relationship to the left without altering peak tetanicforce, resulting in increased force at stimulation frequencies 50 Hz.During 20-Hz intermittent stimulation, DAP increased diaphragm peakforce compared with control during a 150-s fatigue run and,furthermore, significantly improved maintenance of intratrain force.The relative contribution of neurotransmission failure to fatigue wasestimated by comparing the force generated by phrenic nerve-stimulatedmuscles with that generated by curare-treated field-stimulated muscles.DAP significantly increased force in nerve-stimulated muscles and, inaddition, reduced the neurotransmission failure contribution todiaphragm fatigue. Thus DAP increases muscle force atlow-to-intermediate stimulation frequencies, improves overall force andintratrain fatigue during 20-Hz intermittent stimulation, and reducesneurotransmission failure.

     

Myasthenia Gravis: Anesthetic and Surgical Management of the Patient Undergoing Thymectomy

Experience in the anesthetic and surgical management of 25 patients with myasthenia gravis is recorded. These are subdivided into two groups: those operated on during the period 1950-1958 and those operated on during the period 1959-1964. The purpose of this paper is to indicate improvement in mortality and morbidity due to three major advances: (1) use of the decamethonium diagnostic test in a myasthenia gravis clinic; (2) improvements in assessment and management of respiratory insufficiency; and (3) avoidance of anticholinesterase treatment in the immediate and early postoperative recovery period.Fourteen patients with myasthenia gravis, including five with thymoma and two who were refractory to medication, were in the second (1959-1964) group. There were no deaths and no myasthenic or cholinergic crises. Three prophylactic tracheostomies were performed. No emergency bronchoscopies or tracheostomies were required.     

Interaction of myasthenic serum globulin with the acetylcholine receptor.

A serum factor from patients with myasthenia gravis which inhibited the binding of 125I-labeled alpha-bungarotoxin to acetylcholine receptor extracted with Triton X-100 from rat muscle has been studied in detail. The inhibitory activity was localized to the IgG fraction based upon the fractionations by sodium sulfate precipitation and DEAE chromatography as well as reaction with anti-IgG globulin. The myasthenic globulin inhibited toxin binding to receptors extracted from degenerated muscle but did not inhibit toxin binding to normal junctional receptors. At saturation levels of myasthenic globulin, the number of denervated acetylcholine receptors available for toxin binding was reduced approx. 50 percent. The myastehnic globulin was found to bind to denervated acetylcholine receptors but not to normal acetylcholine receptors by a radioimmunoassay technique in which myasthenic globulin incubated with 125I-labeled alpha bungarotoxin-receptor complexes was precipitated by anti-IgG serum. The globulin binding was saturable over the same range as inhibition of toxin binding. The data suggest that the myasthenic IgC binds to a site on the receptor complex juxtaposed to the acetylcholine receptor site. The myasthenic globulin appears to be a useful probe for investigation differences between acetylcholine receptors extracted from normal and denervated muscle and for investigating the pathogenesis of myasthenia gravis.     

Effect of amiloride on diaphragmatic contractility: evidence of a role for Na(+)-Ca2+ exchange

Extracellular Ca2+ has been shown to be important for the normal function of the diaphragm. In this study we have examined the potential importance of Na(+)-Ca2+ exchange as a mechanism for Ca2+ influx during the contractile process by studying the effect of inhibition or stimulation of Na(+)-Ca2+ exchange. Blockade of Na(+)-Ca2+ exchange with amiloride attenuated the twitch response, altered the force-frequency response curve, and enhanced the development of fatigue. The effect of amiloride could be partially reversed by increasing the extracellular Ca2+ concentration. The ability of amiloride to decrease force was associated with decreased Ca2+ uptake by the diaphragm. Enhancing intracellular Na(+)-extracellular Ca2+ exchange by inhibiting the Na(+)-K+ pump significantly decreased the rate of the development of muscle fatigue (89%). The maximal inhibition of diaphragmatic force produced by the amiloride analogue benzamil, which possesses 10-fold greater selectivity for Na(+)-Ca2+ exchange, was not significantly different from that produced by amiloride (76.2 +/- 1.1%), with a concentration that decreased maximum force by 50% equal to 46 microM compared with 460 microM for amiloride. Both agents slowed the maximal rate of relaxation up to 90%. Benzamil elevated resting tension during continuous stimulation of the diaphragm at 0.15 Hz. The results suggest that Na(+)-Ca2+ exchange may have a role in the normal function of the diaphragm.     

Reversal of muscle fatigue during 16 h of heavy intermittent cycle exercise.

This study examined the effects of extended sessions of heavy intermittent exercise on quadriceps muscle fatigue and weakness. Twelve untrained volunteers (10 men and 2 women), with a peak oxygen consumption of 44.3 +/- 2.3 ml.kg(-1).min(-1), exercised at approximately 91% peak oxygen consumption for 6 min once per hour for 16 h. Muscle isometric properties assessed before and after selected repetitions (R1, R2, R4, R7, R12, and R15) were used to quantitate fatigue (before vs. after repetitions) and weakness (before vs. before repetitions). Muscle fatigue at R1 was indicated by reductions (P < 0.05) in peak twitch force (135 +/- 13 vs. 106 +/- 11 N) and by a reduction (P < 0.05) in the force-frequency response, which ranged between approximately 53% at 10 Hz (113 +/- 12 vs. 52.6 +/- 7.4 N) and approximately 17% at 50 Hz (324 +/- 27 vs. 270 +/- 30 N). No recovery of force, regardless of stimulation frequency, was observed during the 54 min between R1 and R2. At R2 and for all subsequent repetitions, no reduction in force, regardless of stimulation frequency, was generally found after the exercise. The only exception was for R2, where, at 20 Hz, force was reduced (P < 0.05) by 18%. At R15, force before repetitions for high frequencies (i.e., 100 Hz) returned to R1 (333 +/- 29 vs. 324 +/- 27 N), whereas force at low frequency (i.e., 10 Hz) was only partially (P < 0.05) recovered (113 +/- 12 vs. 70 +/- 6.6 N). It is concluded that multiple sessions of heavy exercise can reverse the fatigue noted early and reduce or eliminate weakness depending on the frequency of stimulation.     

Supraspinal fatigue does not explain the sex difference in muscle fatigue of maximal contractions.

Young women are less fatigable than young men for maximal and submaximal contractions, but the contribution of supraspinal fatigue to the sex difference is not known. This study used cortical stimulation to compare the magnitude of supraspinal fatigue during sustained isometric maximal voluntary contractions (MVCs) performed with the elbow flexor muscles of young men and women. Eight women (25.6 +/- 3.6 yr, mean +/- SD) and 9 men (25.4 +/- 3.8 yr) performed six sustained MVCs (22-s duration each, separated by 10 s). Before the fatiguing contractions, the men were stronger than the women (75.9 +/- 9.2 vs. 42.7 +/- 8.0 N.m; P < 0.05) in control MVCs. Voluntary activation measured with cortical stimulation before fatigue was similar for the men and women during the final control MVC (95.7 +/- 3.0 vs. 93.3 +/- 3.6%; P > 0.05) and at the start of the fatiguing task (P > 0.05). By the end of the six sustained fatiguing MVCs, the men exhibited greater absolute and relative reductions in torque (65 +/- 3% of initial MVC) than the women (52 +/- 9%; P < 0.05). The increments in torque (superimposed twitch) generated by motor cortex stimulation during each 22-s maximal effort increased with fatigue (P < 0.05). Superimposed twitches were similar for men and women throughout the fatiguing task (5.5 +/- 4.1 vs. 7.3 +/- 4.7%; P > 0.05), as well as in the last sustained contraction (7.8 +/- 5.9 vs. 10.5 +/- 5.5%) and in brief recovery MVCs. Voluntary activation determined using an estimated control twitch was similar for the men and women at the start of the sustained maximal contractions (91.4 +/- 7.4 vs. 90.4 +/- 6.8%, n = 13) and end of the sixth contraction (77.2 +/- 13.3% vs. 73.1 +/- 19.6%, n = 10). The increase in the area of the motor-evoked potential and duration of the silent period did not differ for men and women during the fatiguing task. However, estimated resting twitch amplitude and the peak rates of muscle relaxation showed greater relative reductions at the end of the fatiguing task for the men than the women. These results indicate that the sex difference in fatigue of the elbow flexor muscles is not explained by a difference in supraspinal fatigue in men and women but is largely due to a sex difference of mechanisms located within the elbow flexor muscles.     

Diaphragmatic fatigue in the rat

We studied fatigue of rat diaphragm in response to repetitive brief and prolonged electrical stimulation of the phrenic nerve, at 0.2, 1-100 Hz. Low and high frequency of stimulation produced twitch and tetanic contractions in the rat diaphragm. A mean maximum twitch tension of 1.4 +/- 0.1 g was produced at 1 Hz, and a mean maximum tetanic tension of 5.6 +/- 0.3 g was obtained at 100 Hz (means +/- S.E., n = 8). Twitch and tetanic fatigue was produced at all frequencies of stimulations, but with different time scale, or duration, and with different number of stimuli delivered to the muscle. At low rates of stimulation, e.g. 10 Hz, fewer stimuli were needed to fatigue the muscle (3000 in 5 min), whereas at high rates of stimulation, e.g. 50 Hz, more stimuli were needed to fatigue the muscle (6600 in 2.2 min). The amplitude of the tetanic tensions elicited at 10 and 50 Hz, at the end of 5 or 2 min fatiguing stimulation, was 39 +/- 2.7% and 80 +/- 3.1% of their respective control tensions (2.8 +/- 0 2 g and 5.3 +/- 0.5 g, n = 8, P 0.001). It was concluded that fatigue in the rat diaphragm depended on the frequency and duration of stimulation as well as on the number of stimuli delivered to the muscle. Various mechanisms of muscle fatigue are described in the discussion to explain the observations made in the present investigation.