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Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We tested the hypothesis that the mechanisms involved in the more rapid onset of fatigue when O2 availability is reduced in contracting skeletal muscle are similar to those when O2 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 Ca2+ concentrations ([Ca2+]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 PO2 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-PO2 treatments (280 ± 38 s). Relative [Ca2+]c was significantly decreased from maximal values at the fatigue time point during both the high- (72 ± 4%) and low-PO2 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-PO2 treatments (82 ± 3%), with no significant difference between treatments. Additionally, there was no significant difference in relative [Ca2+]c between the high- (100 ± 12% of prefatigue values) and low-PO2 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 PO2 condition was modulated through similar pathways as the fatigue process during the high and involved a decrease in relative peak [Ca2+]c.
oxidative phosphorylation; exercise; contractions; caffeine; relaxation; excitation-contraction coupling
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE CAUSES OF MUSCLE FATIGUE have been examined in great detail (see Refs. 6, 33, 34), and research has indicated that processes within the muscle (as opposed to neural mechanisms) are of greatest importance in the generation of fatigue during relatively high-intensity work (33). It has been suggested (30) that fatigue during high-intensity exercise occurs when an imbalance develops between the ATP demand of the ATPases and the ATP production by oxidative phosphorylation and glycolysis. It is unclear, and likely variable, whether this ATP supply-demand imbalance is a result of inadequate mitochondrial concentration, substrate limitation (NADH, Pi, ADP) to the working mitochondria, or inadequate availability of O2 as the electron acceptor at the terminal end of oxidative phosphorylation. It has been demonstrated that in working whole muscle, the onset of fatigue occurs sooner in ischemic or hypoxic hypoxia conditions than in normoxia (3, 15, 16). It is unknown whether the resulting decline of muscle force during O2-limited conditions, when muscle respiration is compromised, occurs by different mechanisms than muscle fatigue during conditions when O2 availability is more sufficient.
Recent work (2, 21, 22, 32) has suggested that failure of excitation-contraction (E-C) coupling is a main factor that causes loss of tension development during the fatigue process. Direct measurements of free cytosolic Ca2+ concentration ([Ca2+]c) in single muscle fibers have provided evidence that reduced Ca2+ release from the sarcoplasmic reticulum (SR) is the primary factor behind the failure (1, 2, 22, 31). In addition, a reduced Ca2+ sensitivity and impaired cross-bridge cycling have been implicated in the decrease in contractility associated with fatigue (22, 35). Caffeine has been shown to increase the release of Ca2+ from the SR (26) and to increase myofilament Ca2+ sensitivity and therefore has been used to investigate the effects of fatigue on contractility. When caffeine was applied to severely fatigued frog (20, 24) and mouse single fibers (2, 21), tension was increased to ~80% of the initial maximum tension, demonstrating that the SR was intact but was suffering a depressed release of Ca2+. It remains uncertain what factors modulate this impaired Ca2+ metabolism.
To investigate whether the force producing impairment that occurs in working muscle during O2-limited conditions operates through a similar E-C coupling failure mechanism as under higher O2 availability conditions, we performed two series of experiments in isolated single Xenopus muscle fibers. In the first series, relative [Ca2+]c and force were simultaneously measured during an incremental fatiguing work protocol under conditions of high and low extracellular PO2. In the second series, we compared the effects of 5 mM caffeine application on tension development in fibers subjected to the same fatiguing work protocol and varied extracellular PO2 as during the first series.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Two methodologies were employed to investigate the role of cytosolic Ca2+ in fatigue during O2-limited conditions. In the first series of experiments, fibers (n = 6) were subjected to a fatiguing work protocol during conditions of high and low PO2 while measurements of force and relative [Ca2+]c were simultaneously collected. In the second series, different fibers (n = 6) were subjected to the same high- and low-PO2 exercise protocol, but 5 mM caffeine were applied to the working preparation when the fatigue point was reached.
Experimental preparation. Adult female Xenopus laevis were doubly pithed and decapitated. Lumbrical muscles 2-4 were removed, and single living muscle fibers were microdissected from the muscle. Dissections and experiments were performed in Ringer solution (112 mM NaCl, 1.87 mM KCl, 0.82 mM CaCl2, 2.38 mM NaHCO3, 0.07 mM NaH2PO4, 1.0 mM EGTA) at 20°C and 7.0 pH. After dissection, platinum clips were attached to the tendons, and the fibers were mounted in a glass chamber and placed on the stage of an inverted microscope configured for epi-illumination.
Tetanic contractions were induced by direct stimulation (50 impulses/s of 1-ms duration at 9 V, with a train duration of 200 ms) with platinum conducting electrodes on either side of the fiber, by using a Grass S48 stimulator (Quincy, MA). Force development was measured with a force transducer system (model 400A, Aurora Scientific, Aurora, ON). A Biopac Systems MP100WSW (Santa Barbara, CA) analog-to-digital converter was used to transform the analog force signal, and the digital data were collected and analyzed with AcqKnowledgeIII 3.2.6 software (Biopac Systems).Experimental protocol. In both series of experiments, fibers were stimulated at increasing frequencies (0.25, 0.33, 0.5, and 1 contraction/s) in a sequential manner with each stimulation frequency lasting 2 min. Low-PO2 Ringer perfusate was generated by aeration with 95% N2-5% CO2 until the desired PO2 was achieved, and high-PO2 was maintained by aeration with 21% O2-5% CO2-balance N2. The PO2 of the Ringer solution in the chamber was monitored with a Clark-style electrode (model 733, Diamond General, Ann Arbor, MI) placed adjacent to the working fiber. Each fiber had its rate of fatigue development measured during two separate work bouts (with 45 min of rest between) with the perfusate PO2 switched between the high- and low-PO2 conditions. Both orders of oxygenation were incorporated equally. Constant perfusion was maintained during each contractile period to maintain the experimental PO2 and to reduce the possible occurrence of unstirred layers surrounding the cell. Fatigue was determined as the time point at which the development of force had declined to 50% of the initial maximum tension.
Ca2+ fluorescence. Relative [Ca2+]c was obtained by using fluorescence spectroscopy. Fibers (n = 6) were pressure injected with the Ca2+ indicator fura 2 (F-1200, Molecular Probes). Injected fibers were illuminated with two rapidly alternating (20-Hz) excitation wavelengths of 340 and 380 nm, and the resulting fluorescence emissions at 510 nm were divided (340 nm/380 nm) to obtain the Ca2+-dependent signal (10). Fluorescence was measured with a Photon Technology International illumination and detection system (DeltaScan model), integrated with a Nikon inverted microscope with a ×40 Fluor objective.
Caffeine protocol. Deoxygenated Ringer solution containing 5 mM caffeine was prepared isosmotically by decreasing the relative concentration of the primary solutes and was applied dropwise to the working preparation when force development was reduced to ~50% peak tension. Immediately after maximal tetanic contractions in the presence of caffeine (~5-7 contractions), stimulation was terminated to prevent cellular injury, and the caffeinated Ringer solution was removed by flushing the system.
An adjunct experiment was performed on a separate set of single fibers (n = 6) in which relative [Ca2+]c measurements and force were obtained simultaneously during the application of caffeine, to ensure that caffeine generated an increase in [Ca2+]c to prefatigue levels. In these experiments, caffeine was applied to three fibers during fatigue in the high-PO2 treatment and three during the low. Force increases due to caffeine application in both experiments were compared to ensure similar levels of activation.Measurements. Cross-sectional area was determined by averaging the three largest and three smallest measured radii. Force transduction was converted from volts to newtons by calibrating the force transducer system with a series of weights. Tension was recorded in units of force per cross-sectional area (kPa). All waveform analyses were performed by using AcqKnowledgeIII software. Individual peak tensions were compared with the highest peak tension within that work run.
Relative [Ca2+]c measurements were standardized in a similar fashion. Five individual 340 nm/380 nm excitation ratios (peak [Ca2+]c) were averaged at each measurement time point (consecutive 60-s intervals after the onset contractions) and compared with the average of the five highest ratios within that run. Relative resting Ca2+ measurements (340 nm/380 nm baseline) were averaged in a similar fashion and compared with the lowest resting levels within that run.Statistics. Two-way repeated-measures analysis of variance was performed for the statistical analysis. In all analyses, the 0.05 level of significance was used. Results are reported as means ± SE.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Ca2+ measurements.
The PO2 was maintained at 22 ± 1.7 Torr for the duration of the low-extracellular
PO2 fatigue run and 159 Torr during
the high. Figure 1 illustrates
a typical fatigue run for a single muscle fiber subjected to both high-
and low-PO2 treatments, in which
force and relative [Ca2+]c were
simultaneously measured.
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Caffeine experiments.
Fatigue was reached significantly sooner during the low- (237 ± 38 s)
than during the high-PO2 treatments
(299 ± 27 s). Tetanic contractions in the presence of caffeine
generated an immediate and significant increase in tension development
in all fibers. Figure 4 illustrates that
caffeine enhanced force potentiation to 82 ± 3% of peak force during
the high-PO2 treatment, which was not
significantly different from the 89 ± 4% force potentiation during
the low PO2 treatment.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study demonstrated that an earlier onset of fatigue associated with reduced O2 availability in isolated single skeletal muscle fibers was mediated through similar pathways as when O2 availability was not limited and involved a decrease in relative peak [Ca2+]c.
Muscle fatigue. As work intensity increases in contracting muscle, metabolism increases to meet the elevated ATP demand. After the immediate increase in demand is met by PCr hydrolysis, increases in the rate of glycolysis and oxidative phosphorylation maintain the supply-demand balance. It has been postulated that during high-intensity work (30), fatigue occurs when these phosphorylating pathways become insufficient to maintain the supply-demand balance of ATP and force (demand) is downregulated to preserve intracellular ATP levels (12). The causes of fatigue in contracting muscle have been well studied and are varied (see Refs. 6, 33, 34). Loss of developed tension under high-intensity-exercise conditions has been attributed to failure of E-C coupling within the myocyte (19) and may be associated with an accumulation of metabolites (H+, Pi, etc.) that can directly inhibit the contractile apparatus (8, 9, 29) or disrupt the Ca2+-release and -uptake pathways in the SR (4, 23, 25, 33).
It remains uncertain as to the causes of the inadequate ability of ATP production to meet the ATPase demand during high-intensity contractions. Muscle mitochondrial concentration may be insufficient, the various substrates of oxidative phosphorylation may become limiting, and it is clear that under some conditions the amount of O2 available to the mitochondria may be inadequate. In exercising humans (17, 18) and in whole muscle models (13, 15), hypoxic hypoxia has been shown to reduce the time to contractile failure. When O2 availability is rate limiting to mitochondrial respiration, working muscle has the capacity to reduce force production to the level at which the ATPase rate is well matched to the O2 availability for oxidative phosphorylation (14). In addition, we have demonstrated that even at similar rates of mitochondrial respiration, the relationship of mitochondrial substrates (Pi, ADP) to respiration and force development may be altered by O2 availability (11, 12, 16). It is unknown whether the reduction of force production during O2-limited conditions is mediated through different factors than the fatigue process that occurs under conditions when O2 is not limiting to mitochondrial respiration. In the isolated single fiber model used in the present study, specific conditions can be accurately set by adjusting the extracellular environment. O2 availability to the mitochondria was determined solely by diffusive concerns and manipulated by altering the PO2 of the surrounding medium. The extracellular PO2 was uniform around the fiber, which is somewhat different from in vivo conditions, where whole muscle fibers are surrounded by a vascular network with a varied PO2 from arterial to venous circulations. Thus, in vivo, O2 availability at the cellular level is very heterogeneous, making a determination of the actual O2 available to the mitochondria difficult to determine (5). In addition, the isolated cells used in the present study do not contain myoglobin so that facilitated transport of O2 within the cell is not present (as opposed to mammalian cells). However, because the present experiments were performed in amphibian skeletal muscle fibers at 20°C, some differences in metabolic flux and demand may exist between the present system and mammalian systems functioning at 37°C. Additionally, it has been recently noted in skinned muscle fiber preparations that some aspects of Ca2+ handling, in particular, differences in the significance of Ca2+-induced Ca2+ release from the SR, may exist between the two systems (27). Although this, along with the difference in myoglobin content, may influence the extrapolation of metabolic functionality from amphibian to mammalian systems, the similarities in muscle function between these systems is strong, as indicated by substantial work previously conducted in this area using both systems (22, 23, 31, 32).Contractility and Ca2+ metabolism. A disruption in E-C coupling has been associated with the fatigue process, and recent work measuring [Ca2+]c in single muscle fibers during fatiguing stimulation (22, 35) has primarily attributed this to decreased Ca2+ release from the SR. The disruption in E-C coupling associated with fatigue can be overcome by the application of caffeine, which has been used in the single fiber preparation to demonstrate SR functionality (20, 21, 24). Westerblad and Allen (31) applied caffeine to working single mouse fibers when force had declined to <30% initial peak tension, observing an ~80% (tension/peak tension = 0.8) force potentiation, accompanied by a rise in [Ca2+]c. These experiments elegantly demonstrated the intactness of the contractile machinery during fatigue. The reduced affinity of the myofibrils for Ca2+ (22, 35) and impaired cross-bridge function during fatigue (20) have been hypothesized as factors in preventing a full (tension/peak tension = 1) caffeine enhanced potentiation (33).
In the present study, to determine whether the contractile failure during fatigue induced by clear O2 limitation is mechanistically similar to the E-C coupling failure associated with fatigue as when O2 is freely available, two series of experiments were performed in single Xenopus skeletal muscle fibers. In the first series of experiments, relative force and relative [Ca2+]c measurements were obtained simultaneously (Fig. 1) during fatiguing stimulation in both O2-limited and -unlimited conditions. In the second series of experiments, caffeine was applied to working single fibers after the fatigue point (tension/peak tension = 0.5) was reached, during conditions of high and low extracellular PO2. In the first series of experiments, fatigue occurred significantly earlier (P < 0.05) during the low- compared with the high-extracellular-PO2 condition (Fig. 2), demonstrating an impaired performance associated with decreased O2 availability, as has been previously demonstrated (28). Relative peak [Ca2+]c during fatigue fell in a manner similar to previous findings (22, 35) during both the high- and low-PO2 treatments (Fig. 2). No significant difference was observed at the fatigue point in relative peak [Ca2+]c between the two extracellular PO2 conditions, providing evidence of a similar impaired SR Ca2+ release in both the O2-limited and -unlimited conditions (Fig. 3). Similarly, no significant differences were observed in the relative resting [Ca2+]c between conditions (Fig. 3). In the second series of experiments, application of caffeine resulted in a significant but incomplete force restoration during both treatments, similar to findings by Allen and Westerblad (2) and Westerblad and Allen (31). No significant difference was observed in the caffeine-enhanced force recovery between the high- and low-PO2 treatments (Fig. 4), providing evidence of impaired E-C coupling associated with the fatigue process during both the low and high extracellular PO2 treatments. The incomplete force recovery after application of caffeine suggests that either the caffeine-induced release of Ca2+ from the SR was incomplete and/or there is evidence of reduced Ca2+ sensitivity and impaired cross-bridge cycling. To investigate this, an adjunct series of experiments was performed in which [Ca2+]c was measured during application of caffeine during fatigue in both high- and low-PO2 conditions. A complete recovery in peak [Ca2+]c to prefatigue levels after caffeine administration was observed during both treatments (Fig. 5), demonstrating that the incomplete recovery of force after the application of caffeine was similar during both treatments and was probably not due to an incomplete release of Ca2+ from the SR. Caffeine has been shown to increase the myofilament Ca2+ sensitivity (7), suggesting that perhaps the incomplete recovery in force observed after caffeine application in both the high- and the low-extracellular PO2 treatments may be due to an impairment in cross-bridge cycling associated with increased metabolites (H+, Pi) (6, 20).Conclusions. In summary, the results of this study demonstrated in single Xenopus skeletal muscle fibers that 1) when fibers were subjected to identical fatiguing work protocols, fatigue was reached significantly earlier at an extracellular PO2 of 22 Torr than at 159 Torr; 2) at the fatigue point (tension/peak tension = 0.5), relative peak [Ca2+]c was significantly decreased and relative resting [Ca2+]c was significantly increased, with no difference between the high- and the low-PO2 treatments; 3) application of caffeine to contracting single fibers during the fatigue period caused a significant but incomplete force potentiation in both the high- and low-PO2 treatments, with no significant difference between treatments; and 4) measurements of relative [Ca2+]c during application of caffeine demonstrated a complete restoration of peak [Ca2+]c to prefatigue levels, suggesting an associated cross-bridge cycling impairment. These results demonstrated that the mechanisms causing the faster reduction of force development during O2-limited conditions were regulated by a similar failure in E-C coupling as when O2 availability was more sufficient and suggest both depression of Ca2+ release from the SR and an associated impairment of cross-bridge cycling as the principle causes of contraction failure in both conditions.
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ACKNOWLEDGEMENTS |
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This research was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-40155.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. C. Hogan, Dept. of Medicine, 0623-A, Univ. of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0623 (E-mail: mchogan{at}ucsd.edu).
Received 21 August 1999; accepted in final form 11 January 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Rob. S. James, R. S. Wilson, and G. N. Askew Effects of caffeine on mouse skeletal muscle power output during recovery from fatigue J Appl Physiol, February 1, 2004; 96(2): 545 - 552. [Abstract] [Full Text] [PDF]
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 S. Kohin, C. M. Stary, R. A. Howlett, and M. C. Hogan Preconditioning improves function and recovery of single muscle fibers during severe hypoxia and reoxygenation Am J Physiol Cell Physiol, July 1, 2001; 281(1): C142 - C146. [Abstract] [Full Text] [PDF]
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R. A. Howlett, C. M. Stary, and M. C. Hogan Recovery of force during postcontractile depression in single Xenopus muscle fibers Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1469 - R1475. [Abstract] [Full Text] [PDF]
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, Fatigue time point for
high-PO2 condition; 
, fatigue time
point for low-PO2 condition. Note
that fatigue (tension/peak tension = 0.5) occurred significantly faster
during low- than during high-PO2
treatments. * Significant differences between treatments, P < 0.05.
