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J Appl Physiol 99: 308-312, 2005. First published March 10, 2005; doi:10.1152/japplphysiol.01361.2004
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Intracellular pH during sequential, fatiguing contractile periods in isolated single Xenopus skeletal muscle fibers

C. M. Stary and M. C. Hogan

Department of Medicine, University of California, San Diego, La Jolla, California

Submitted 8 December 2004 ; accepted in final form 3 March 2005


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The purpose of the present study was to test the hypothesis that a preceding contractile period in isolated single skeletal muscle fibers would attenuate the decrease in pH during an identical, subsequent contractile period, thereby reducing the rate of fatigue. Intact single skeletal muscle fibers (n = 9) were isolated from Xenopus lumbrical muscle and incubated with the fluorescent cytosolic H+ indicator 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) AM for 30 min. Two identical contractile periods were performed in each fiber, separated by a 1-h recovery period. Force and intracellular pH (pHi) fluorescence were measured simultaneously while fibers were stimulated (tetanic contractions of 350-ms trains with 70-Hz stimuli at 9 V) at progressively increasing frequencies (0.25, 0.33, 0.5, and 1 contraction/s) until the development of fatigue (to 60% initial force). No significant difference (P < 0.05) was observed between the first and second contractile periods in initial force development, resting pHi, or time to fatigue (5.3 ± 0.5 vs. 5.1 ± 0.6 min). However, the relative decrease in the BCECF fluorescence ratio (and therefore pHi) from rest to the fatigue time point was significantly greater (P < 0.05) during the first contractile period (to 65 ± 4% of initial resting values) compared with the second (77 ± 4%). The results of the present study demonstrated that, when preceded by an initial fatiguing contractile period, the rise in cytosolic H+ concentration in contracting single skeletal muscle fibers during a second contractile period was significantly reduced but did not attenuate the fatigue process in the second contractile period. These results suggest that intracellular factors other than H+ accumulation contribute to the fall in force development under these conditions.

anaerobic metabolism; glycolysis; oxidative phosphorylation; phosphocreatine; fluorescence; onset kinetics; exercise

IT HAS BEEN PREVIOUSLY DEMONSTRATED in whole skeletal muscle that a preceding bout of exercise increases the onset kinetics of oxidative phosphorylation during the rest-to-work transition (7, 19). Whether the increase in the rate of O2 utilization (O2) was due to cardiovascular (global) and/or microvascular (local) responses resulting in an increased O2 availability, or to "priming" of intracellular regulators of oxidative metabolism remains controversial (24). However, we have previously demonstrated in isolated whole muscle that increases in O2 delivery do not positively modulate the O2 onset kinetics during submaximal exercise (9, 10). Furthermore, we have recently demonstrated in isolated single skeletal muscle fibers (thereby eliminating vascular O2 delivery considerations) that a more rapid increase in the onset kinetics of oxidative metabolism occurs during a second contractile period at the same extracellular PO2 (12). These results suggest that regulation of the onset kinetics of oxidative phosphorylation during submaximal exercise is likely determined by intracellular enzymatic processes, and not by O2 availability per se.

At the onset of high-intensity contractions, energy demand is closely coupled with energy supply from rephosphorylation of ATP, supplied through oxidative metabolism and substrate-level metabolism [phosphocreatine (PCr) hydrolysis and anaerobic glycolysis]. Therefore, even a minor increase in the speed of onset kinetics of O2 should be met with a large decrease in reliance on substrate-level phosphorylation for resynthesis of ATP (due to the greater efficiency of ATP production per unit substrate of aerobic metabolism), and thus generation of lactic acid for a given energy demand should be reduced. Intracellular lactic acid readily dissociates into lactate and H+ ion in the cytosol, and increases in cytosolic H+ concentration ([H+]cyt) have been closely associated with fatigue in many experimental models (5, 6). However, whether increased [H+]cyt is the primary agent responsible for the decrease in force production during fatigue remains controversial (5, 6, 27, 29). To test the hypothesis that a previous contractile period results in an attenuation of [H+]cyt generation, resulting in an increased time to fatigue, we subjected isolated single skeletal muscle fibers to a series of two identical fatiguing contractile periods, separated by an hour of recovery, while simultaneously measuring force and intracellular pH (pHi)-dependent fluorescence.


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Experimental preparation.   All procedures were approved by the University of California San Diego Animal Use and Care Committee and conform to National Institutes of Health Standards. Single fibers were prepared as previously described (22). Briefly, adult female Xenopus laevis were doubly pithed and decapitated. Lumbrical muscles II–IV were removed, and single living muscle fibers (n = 9) 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, 0.1 mM EGTA) at 20°C and 7.0 pH, equilibrated with 21% O2 and 3% CO2 (balance N2). After dissection, cross-sectional area was determined for each fiber by measuring the smallest and largest diameter with use of a standardized eyepiece reticle. Platinum clips were then attached to the tendons, and individual fibers were mounted in a glass chamber and placed on the stage on an inverted microscope configured for epi-illumination. During the experimental protocol, individual fibers were constantly perfused with Ringer solution to prevent the occurrence of any unstirred layers surrounding the fiber.

Tetanic contractions were induced by direct stimulation (70 impulses/s of 1-ms duration at 9 V, with a train duration of 350 ms) with platinum conducting electrodes on either side of the fiber, using a Grass S48 stimulator (Quincy, MA). Force development was measured with a force transducer system (Aurora Scientific, model 400A, Aurora, Ontario, Canada). 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 version 3.5 software (Biopac Systems).

pHi fluorescence.   Relative changes in pHi were obtained by use of pHi-dependent fluorescence spectroscopy. Fibers were incubated with 10 µM of the membrane-permeant acetoxymethyl ester form of the [H+]cyt indicator 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF; Molecular Probes). Incubated fibers were illuminated with two rapidly alternating (20 Hz) excitation wavelengths of 440 and 490 nm, and the resulting fluorescence emission intensities at 535 nm were divided (490 nm/440 nm) to obtain the pHi-dependent signal (25). Absolute resting pHi was standardized by perfusing with 10 µM of the K+/H+ ionophore nigiricin in KCl-buffered (140 mM) Ringer and calibrating with three pH-standardized solutions in series: pH 6.5, 7.0, and 7.5 (25). Fluorescence was measured with a Photon Technology International illumination and detection system (DeltaScan model), integrated with a Nikon inverted microscope with a x40 Fluor objective.

To determine whether relative changes in the BCECF fluorescence ratio were physiological and not due to a spectroscopic artifact such as photobleaching, we monitored fluorescence in noncontracting cells (n = 3) for the duration of the experimental protocol. No significant change in the ratio of emitted light was detected over the course of the measurement period, as has been previously demonstrated in single skeletal muscle fibers (25).

Experimental protocol.   Each fiber was subjected to a series of two identical experiments performed in sequence, separated by a 1-h recovery period. This recovery period was necessary to ensure that fatigued fibers recovered fully from "postcontractile depression," a phenomenon observable in these single fibers (17, 27, 29). 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. For each fiber, force development and BCECF fluorescence were measured until the fatigue time point (time at which force production was 60% initial maximum force) was surpassed.

Statistics.   Two-way repeated-measures analysis of variance was performed for the statistical analysis. In all analyses, a 0.05 level of significance was used. Results are reported as means ± SE.


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No significant difference (P < 0.05) in initial maximal force development was measured between the first (295 ± 35 kPa) and second (240 ± 34 kPa) contractile periods for all fibers (n = 9). Representative force and BCECF fluorescence recordings for the two consecutive fatiguing contractile periods for a single cell are illustrated in Fig. 1.



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  		Fig. 1. Example of force and 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) fluorescence recordings during 2 consecutive, fatiguing contractile periods for an isolated single skeletal muscle fiber. In this figure, a decrease in the fluorescence ratio corresponds with a decrease in intracellular pH.

 
Figure 2 demonstrates mean relative force development throughout the two contractile protocols for all fibers. After the onset of contractions, no significant difference (P < 0.05) in force production was observed between treatments throughout the contractile protocol. Similarly, no significant difference was observed in the time to fatigue point between the first (5.3 ± 0.6 s) and second (5.1 ± 0.6 s) contractile periods.



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  		Fig. 2. Relative force for 2 consecutive fatiguing contractile periods in single skeletal muscle fibers (n = 9, means ± SE). Note the absence of significant difference (P < 0.05) between contractile periods at any time point.

 
Figure 3 illustrates relative changes in the BCECF fluorescence ratio (and therefore pHi) during the two consecutive contractile periods for all fibers. No significant difference (P < 0.05) in the absolute resting pH before contractions was observed between the first (pH 7.1 ± 0.09) and second treatments (pH 7.1 ± 0.09), indicating complete recovery of pHi between trails. After the onset of contractions, all fibers exhibited a significant increase in the BCECF fluorescence ratio indicative of PCr hydrolysis. The initial relative increase in the BCECF fluorescence ratio observed during the second contractile period (by 2 ± 0.4%) was smaller than the first (3 ± 0.4%), although not statistically significant (Fig. 3). The smaller change in pHi, after the onset of contractions during the second contractile period, would be consistent with less PCr hydrolysis needed for ADP rephosphorylation and thereby indicative of a faster onset of oxidative phosphorylation. After this initial alkalosis period, the BCECF fluorescence ratio significantly decreased in all fibers until the fatigue end point. However, the relative decrease in the BCECF fluorescence ratio from rest to fatigue (Fig. 3) was significantly greater (P < 0.05) during the first contractile period (to 65 ± 4% of initial resting levels) compared with the second contractile period (77 ± 4%).



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  		Fig. 3. Relative changes in the BCECF fluorescence ratio (indicative of intracellular pH) for consecutive fatiguing contractile periods in single skeletal muscle fibers (n = 9, means ± SE). *Significant difference (P < 0.05).

 

   DISCUSSION
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The results of this study demonstrate in single skeletal muscle fibers subjected to two sequential fatiguing contractile periods that 1) the decrease in pHi during the second contractile period was significantly attenuated relative to the first, suggesting better maintenance of intracellular homeostasis during the second contractile period, and 2) no significant difference in the time to fatigue was observed between the first and second contractile periods, suggesting that accumulation of H+ in the cytosol is not the major factor in the generation of fatigue under the conditions of this study.

Metabolic response to onset of exercise.   At the onset of the transition from rest to high-intensity contractions in skeletal muscle, ATP demand can increase several hundredfold. In skeletal muscle, an increase in ATP demand is closely matched with elevated ATP resynthesis from increased activity of the primary metabolic pathways: substrate level phosphorylation (PCr hydrolysis and anaerobic glycolysis) and oxidative phosphorylation, with the predominant pathway determined by the intensity and duration of exercise. It has been previously determined in the single muscle fibers used in the present study that demand for ATP is initially met by substrate-level phosphorylation, followed by a subsequent progressive increase in oxidative phosphorylation (3, 20). The duration of PCr hydrolysis is of short duration and limited by PCr availability (14), and ATP resynthesis is supplemented by anaerobic glycolysis until oxidative phosphorylation can achieve a rate suitable to meet the ATP demand (3).

The factors that determine the onset rate of oxidative phosphorylation remain unclear (24). Recently we have demonstrated that increases in the delivery of O2 to isolated whole skeletal muscle during submaximal exercise did not significantly affect the onset kinetics of oxidative phosphorylation after the rest-to-work transition, suggesting that O2 onset kinetics may be regulated primarily by intracellular factors (9, 10). One intracellular mechanism potentially involved in limiting the onset rate of O2 is the rate of activation of pyruvate dehydrogenase (PDH). There is evidence that, before exercise, activation of PDH by dichloroacetate may accelerate O2 onset kinetics at submaximal intensities (15, 23), implying an increased O2 onset kinetics. However, it has also been demonstrated that application of dichloroacetate does not significantly affect markers of anaerobic metabolism at maximal work intensities, suggesting that PDH activation is likely not an influential factor in determining the O2 onset kinetics of contracting skeletal muscle at higher work intensities (1, 15).

A second phenomenon that has been shown to affect the onset rate of O2 is repeated bouts of exercise. For instance, it has been demonstrated in whole muscle and in vivo models that a previous period of contractile activity results in an increase in the onset kinetics of oxidative phosphorylation, suggesting that a previous activation period may "prime" the oxidative metabolic pathway (1, 2, 7, 19). An interesting observation is that this priming effect is only observed when the previous activation period is of sufficient intensity to generate lactic acid accumulation (7), suggesting that elevations in [H+]cyt may be involved in the priming mechanism. However, in the whole muscle and in vivo models used in these studies, factors such as blood flow and fiber-type heterogeneity confound the interpretation of results, making a determination of the intrinsic intracellular elements regulating the onset kinetics of oxidative phosphorylation difficult.

Single fibers.   The isolated single skeletal muscle fiber model used in the present study provides a means of eliminating the problems associated with blood flow and fiber-type heterogeneity found in whole muscle and in vivo models, permitting a more definitive analysis of metabolism at the cellular level. In the single-fiber model used in the present study, the extracellular environment surrounding individual cells was precisely determined and maintained, and O2 availability between treatments was identical. Using a novel intracellular PO2 photometric measurement system (12), we have recently demonstrated in isolated single skeletal muscle fibers that a previous series of contractions results in a more rapid fall in intracellular PO2 during the second series of contractions (11), thereby demonstrating a more rapid activation of oxidative phosphorylation. These findings suggest that, because the onset rate of oxidative metabolism is increased after a previous bout of exercise, the dependence on anaerobic metabolism for ATP resynthesis will be decreased. Therefore, to determine whether the reliance on anaerobic metabolism for ATP resynthesis was indeed decreased after a previous bout of fatiguing contractions, we simultaneously measured force production and pHi-dependent fluorescence in isolated single skeletal muscle fibers during two identical, sequential fatiguing contractile periods (Fig. 1).

Cytosolic pH and force production.   In the present study, no significant difference was observed either in the maximum initial force production or in the development of steady-state force production (Fig. 2). In single muscle fibers similar to those used in the present study (contracting at a similar rate), we have previously demonstrated that, at this contractile frequency, PCr stores alone can supply ATP for only a very limited time (21) before force production is completely abolished. After the onset of contractions, pHi increases as H+ is consumed during PCr hydrolysis, according to the following ATP resynthesis reaction catalyzed by creatine kinase:

(1)
PCr hydrolysis was evident in the present study by the observation in all fibers of an initial period of alkalosis. It is well established that decreased pH is correlated with the attenuation of force production during the fatigue process in both mammalian and amphibian systems (see Refs. 5, 27). However, whether a decrease in pH is the primary factor contributing to reduced force production remains controversial (5, 6, 27, 29). For example, conflicting evidence exists as to whether H+ has the capacity to directly inhibit the contractile apparatus and/or depress Ca2+ release from the sarcoplasmic reticulum (4, 8, 18, 26). Furthermore, it has been determined (28) in single skeletal muscle fibers similar to those used in the present study that large variances in pH occur for a given level of force production and that recovery of tension and restoration of pH after fatigue occur at different rates, suggesting that H+ may contribute less to the attenuation of force production during fatigue than historically considered.

Indeed, the results of the present study appear to confirm the concept that H+ may play a more corollary than causative role in the attenuation of force production in these single skeletal muscle fibers. In the present study, no significant difference was observed in the time to fatigue between the first and second contractile periods (Fig. 2). However, at the fatigue time point, the relative decrease in the BCECF fluorescence ratio (and therefore pHi) during the second treatment was significantly attenuated relative to the first (Fig. 3). This finding suggests that, in these single skeletal muscle fibers, as production of cytosolic H+ appears not to significantly attenuate the production of force, inhibition of force is likely attributable to alternate products of metabolism. Indeed, it has been previously demonstrated in these single fibers that force can be inhibited by increased intracellular concentrations of ADP and Pi (see Ref. 5), as occurs with this degree of fatigue (27, 29).

A second conclusion that may be interpreted from the results of the present study is that, because the production of H+ was decreased during the second treatment relative to the first (Fig. 3), the activity of anaerobic glycolysis plus PCr hydrolysis was likely depressed during the second treatment. This implies that, to maintain an equivalent level of force production (as was demonstrated in Fig. 2), an alternate metabolic system compensated for the decrease in energy for ATP resynthesis from anaerobic glycolysis and PCr hydrolysis. The large yet statistically nonsignificant difference in intracellular alkalosis after the onset of contractions, indicative of the intensity of PCr hydrolysis (Eq. 1), suggests less PCr utilization during the second contractile period. One explanation for these results is that ATP utilization was more economical during the second run. However, this is unlikely because starting conditions surrounding the contractile apparatus (temperature, pH) were unchanged between runs. Therefore, a faster onset rate of oxidative phosphorylation during the second treatment likely provided an increase in energy production, necessary for maintaining steady-state force production, resulting in less disruption of intracellular homeostasis.


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This research was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-40155.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. M. Stary, Dept. of Medicine, 0623-A, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0623 (E-mail: cstary{at}ucsd.edu)

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. Section 1734 solely to indicate this fact.


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