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J Appl Physiol 102: 1456-1461, 2007. First published January 4, 2007; doi:10.1152/japplphysiol.00422.2006 Free Article
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Intracellular PO2 kinetics at different contraction frequencies in Xenopus single skeletal muscle fibers

Richard A. Howlett, Casey A. Kindig, and Michael C. Hogan

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

Submitted 10 April 2006 ; accepted in final form 12 December 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Increasing contraction frequency in single skeletal muscle fibers has been shown to increase the magnitude of the fall in intracellular PO2 (PIO2), reflecting a greater metabolic rate. To test whether PIO2 kinetics are altered by contraction frequency through this increase in metabolic stress, PIO2 was measured in Xenopus single fibers (n = 11) during and after contraction bouts at three different frequencies. PIO2 was measured via phosphorescence quenching at 0.16-, 0.25-, and 0.5-Hz tetanic stimulation. The kinetics of the change in PIO2 from resting baseline to end-contraction values and end contraction to rest were described as a mean response time (MRT) representing the time to 63% of the change in PIO2. As predicted, the fall in PIO2 from baseline following contractions was progressively greater at 0.5 and 0.25 Hz than at 0.16 Hz (32.8 ± 2.1 and 29.3 ± 2.0 Torr vs. 23.6 ± 2.2 Torr, respectively) since metabolic demand was greater. The MRT for the decrease in PIO2 was progressively faster at the higher frequencies (0.5 Hz: 45.3 ± 4.5 s; 0.25 Hz: 63.3 ± 4.1 s; 0.16 Hz: 78.0 ± 4.1 s), suggesting faster accumulation of stimulators of oxidative phosphorylation. The MRT for PIO2 off-kinetics (0.5 Hz: 84.0 ± 11.7 s; 0.25 Hz: 79.1 ± 8.4 s; 0.16 Hz: 81.1 ± 8.3 s) was not different between trials. These data demonstrate in single fibers that the rate of the fall in PIO2 is dependent on contraction frequency, whereas the rate of recovery following contractions is independent of either the magnitude of the fall in PIO2 from baseline or the contraction frequency. This suggests that stimulation frequency plays an integral role in setting the initial metabolic response to work in isolated muscle fibers, possibly due to temporal recovery between contractions, but it does not determine recovery kinetics.

oxidative metabolism; metabolic control; oxygen utilization

OXYGEN UPTAKE (VO2) kinetics, along with skeletal muscle phosphocreatine (PCr) dynamics (30), provide important insights into the regulation of oxidative phosphorylation in skeletal muscle (35). To date, there has been a great deal of research into the mechanisms that may affect these kinetics in a variety of models and with a wide range of interventions. The onset kinetics of VO2 at a given exercise intensity can be altered through several interventions, such as endurance training (15, 32), priming exercise (4, 13, 14), and hypoxia (9) or hyperoxia (27). Studies investigating the effects of pedaling frequency have shown either unchanged (2) or somewhat altered (33) VO2 kinetics as frequency increases. However, interpretation of these results can be difficult due to the effects of fiber-type recruitment likely associated with the VO2 slow component superimposed on the initial fundamental rise in VO2 (12).

Our laboratory has utilized an isolated intact single skeletal muscle fiber preparation in conjunction with real-time phosphorescent measurements of intracellular PO2 (PIO2) to investigate the dynamics of oxidative metabolism during step changes in metabolic demand (16–19, 21–23). Because these Xenopus laevis fibers lack myoglobin, the relationship between VO2 and PIO2 can be described by the Fick equation as:

Formula 1(1)
where extracellular PO2 can be tightly controlled through perfusion of the measuring chamber and Formula 1O2 represents the coefficient of diffusion, a constant within the confines of our experimental setup. Therefore, kinetics of the changes in PIO2 provide an analog of Formula 1O2 kinetics in these single muscle fibers, without many of the confounding factors found in whole body exercise, such as fiber recruitment, fiber-type differences, blood flow heterogeneity, and muscle hemodynamics. It has been previously demonstrated that the kinetics of the fall in PIO2 are very similar to the whole body Formula 1O2 kinetics and that they are sensitive to both priming exercise (16) and the administration of dichloroacetate (18).

Recently, our laboratory showed that the fall in PIO2 was increased ~30% by doubling the duration of the contractile period of isometric tetanic contractions, but the mean response time (MRT) was not altered, and an on/off symmetry existed (21). However, in the aforementioned study (21), the metabolic impulse was evoked at identical contractile frequency (i.e., tetani/s); thus the time between contractile periods was very similar, possibly allowing activation of PCr hydrolysis and glycolysis to contribute to buffering the rise in ADP proportionate to the metabolic demand more closely between trials.

The purpose of the present study was therefore to extend this prior work and investigate the effect of different metabolic demands on PIO2 kinetics by altering the frequency of tetanic contractions while maintaining equal contraction duration. Our hypothesis was that the increased contraction frequency would increase the magnitude of the fall in PIO2 (which is proportional to the rise in Formula 1O2) but that the rate of change in PIO2 would be slower at the lesser contraction frequency, given the additional time to buffer the rise in ADP via PCr hydrolysis.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animal care.   All procedures were approved by the University of California at San Diego animal care and use committee and conformed to National Institutes of Health and American Physiological Society guidelines. Female adult Xenopus laevis were doubly pithed and decapitated, and the lumbrical muscles (II–IV) were dissected free from the hindfeet.

Measurement systems.   All dissections and experiments were conducted at 20°C. Single living muscle fibers (n = 11) were micro-dissected from the lumbrical muscle strips with tendons intact in a chamber filled with Ringer solution (in mM: 112 NaCl, 1.87 KCl, 0.82 CaCl2, 2.38 NaHCO3, 0.07 NaH2PO4, 0.1 EGTA; pH 7.0). Intact cells were microinjected with a solution of 0.5 mM palladium-meso-tetra(4-carboxyphenyl)porphine bound to bovine serum albumin (containing 10 mM fura 2 for visual monitoring) by micropipette pressure injection (World Precision Instruments PV830 pneumatic picopump, Sarasota, FL). Experiments are only performed on fibers with visually intact plasma membrane that exhibit normal contractile properties and do not display any difficulties in propagating action potentials in response to electrical stimulation. No attempt was made to discriminate cells by fiber type.

Phosphorescence signals were recorded using a Nikon x40 Fluor objective (0.70 numerical aperture) used dry. The phosphorescence quenching of the Pd-porphyrin oxygen probe within each cell was measured through a system consisting of a flash lamp (Oxygen Enterprises, Philadelphia, PA), a 425-nm band-pass excitation filter, a 630-nm cut-on emission filter, and a photomultiplier tube for collection of the phosphorescence signal. To calculate phosphorescence lifetimes from the intracellular oxygen probe, the phosphorescent decay curves from a series of 10–15 flashes (15 Hz) were averaged, and a monoexponential function was fit to the subsequent best-fit decay curve (analysis software from Medical Systems, Greenvale, NY). Phosphorescent decay curves were recorded every 4 s from each cell throughout the experimental period. Previously determined values for the measured phosphorescence lifetime decay in a zero-oxygen environment and the phosphorescence quenching constant for the intracellular oxygen probe were used to calculate PIO2 (17). As the oxygen tension decreases in the environment around the porphyrin compound, the phosphorescence lifetime (after a single flash of light) lengthens in a systematic manner (37). This technique has been previously validated for the measurement of PIO2 within single skeletal muscle cells injected with the porphyrin compound (17).

Experimental protocol.   Platinum clips were attached to the tendons of the cells, and they were mounted in a chamber filled with Ringer solution. One end of the fiber was fixed, and the other free end was attached to an adjustable force transducer (Aurora Scientific, model 400A, Aurora, Ontario, Canada), allowing the muscle to be set at a length that produced maximal tetanic peak tension. The analog signal from the force transducer was sampled at 200 Hz and converted to a digital signal via an MP100WSW analog-to-digital converter and analyzed with AcqKnowledgeIII 3.2.6 analysis software (Biopac Systems, Santa Barbara, CA).

To reduce the possible occurrence of unstirred layers surrounding the cell, the chamber was perfused throughout the experimental protocol with Ringer equilibrated with a gas mixture to produce a PO2 of ~40 Torr.

Tetanic contractions were elicited using direct (8–10 V) stimulation of the muscle (Grass model S48, Warwick, RI). Stimulation consisted of 200-ms trains of 70-Hz impulses of 1-ms duration. Following a resting 20-s initial recording period, fibers were stimulated for 2 min at each of 0.16, 0.25, and 0.5 Hz in randomized order. A 15-min recovery period was implemented between all three contraction trials to ensure recovery of peak tension, resting PIO2, and that no priming effect of the previous contraction bout occurred (23) before the subsequent contraction frequency trial was performed.

Calculations.   PIO2 curves for both the on- and off-transients were plotted against time, and the MRT was calculated by determining the time to 63% of the change in PIO2 for each transient. For on-kinetics, this would be determined from the resting baseline PIO2 to the steady-state nadir PIO2. For off-kinetics, this was determined from the steady-state PIO2 immediately following contractions to the new resting baseline value. For all trials, the steady-state value during contractions consisted of four to five data points (16–20 s) when PIO2 was varied by <1 Torr.

Statistics.   All values are presented as means ± SE. To test for significance for each variable, a one-way ANOVA was performed to determine whether differences existed among the three contraction frequencies. When a significant difference was found, a Tukey's least significant difference test was performed post hoc to determine which trials were different. The level of significance was set at P < 0.05 throughout.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
PIO2.   Figure 1 shows the continuous mean (±SE) PIO2 data for all (n = 11) of the isolated single fibers before, during, and following contractile periods for the three experimental trials.


Figure 1
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  		Fig. 1. Mean (±SE) data for all cells (n = 11) representing the on- and off-transients during all three (0.16, 0.25, and 0.5 Hz) experimental trials. The bar represents the period of stimulation for all three contraction frequencies. PIO2, intracellular PO2.

 
Isometric tension.   Figure 2 shows the developed isometric tension at the end of stimulation for all three trials, represented relative to initial developed tension. During the 0.16- and 0.25-Hz conditions, developed tension did not fall significantly (P > 0.05) from the initial value, nor were they different between groups. Conversely, the 0.5-Hz trial showed a significant decrease (P < 0.05) in developed tension compared with both the 0.16- and 0.25-Hz trials.


Figure 2
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  		Fig. 2. Mean (±SE) data for developed isometric tension at the end of the contraction period for each experimental trial. The value represents the mean tension expressed relative to the initial tension at the beginning of the contraction period. *Significantly different from 0.16 Hz (P < 0.05). {dagger}Significantly different from 0.25 Hz (P < 0.05).

 
On-kinetics.   Figure 3 summarizes the mean PIO2 values for the resting baseline, postcontraction, and resultant difference in PIO2 ({Delta}PIO2) for all three trials. In Fig. 3A, the resting, prestimulation PIO2 was not significantly different between groups. Following 2 min of electrical stimulation, the nadir PIO2 was significantly lower in the 0.5- and 0.25-Hz trials than in the 0.16-Hz trial. The resulting difference between resting and contracting levels, or the {Delta}PIO2, was therefore significantly greater in the 0.5- and 0.25-Hz trials vs. the 0.16-Hz trial. In Fig. 3B, despite the larger {Delta}PIO2, the MRT from rest to contracting values was progressively shorter from the 0.16-Hz trial to the 0.5-Hz trial so that all three trials were significantly different.


Figure 3
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  		Fig. 3. A: intracellular PO2 (PIO2) values representing 1) the initial resting value, 2) the final value following contractions, and 3) the magnitude of the difference ({Delta}PIO2) for each of the contraction frequencies. B: the mean response time (MRT) for the fall in PIO2 during the transition from rest to the end of contractile activity at the three experimental contraction frequencies expressed as time to reach 63% of the difference (T63) between rest and steady state. *Significantly different from 0.16 Hz (P < 0.05). {dagger}Significantly different from 0.25 Hz (P < 0.05).

 
Initial metabolic response.   The initial rate of response (calculated as {Delta}PIO2/MRT) was significantly higher in the 0.5-Hz trial than in the 0.25-Hz, whereas the 0.16-Hz trial was lower still (0.82 ± 0.11 vs. 0.48 ± 0.04 vs. 0.32 ± 0.03 Torr/s, respectively).

Off-kinetics.   Figure 4A demonstrates the recovery values for PIO2 from the end of contractions to the new baseline. Mirroring the fall, the initial PIO2 values differed between 0.16 Hz and those at both 0.25 and 0.5 Hz. Since recovery PIO2 was not different between groups, the {Delta}PIO2 was also larger at 0.25 and 0.5 Hz compared with at 0.16 Hz. Figure 4B shows the MRT for increase in PIO2 following the electrical stimulation protocols for all trials. Unlike the on-response, there was no difference in the MRT of the {Delta}PIO2 from poststimulation contracting values to rest in any of the trials.


Figure 4
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  		Fig. 4. A: PIO2 values representing 1) end-contraction value, 2) the final value following recovery, and 3) the magnitude of the difference ({Delta}PIO2) for each of the contraction frequencies. B: MRT for the increase in PIO2 during the recovery from contractile activity at the three experimental contraction frequencies to resting values expressed as time to reach 63% of the difference between nadir PIO2 and rest. *Significantly different from 0.16 Hz (P < 0.05).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
As shown previously (19), the current investigation demonstrates that increasing contraction frequency evokes a larger metabolic demand on the cell as assessed via the magnitude of the fall in PIO2 during electrically stimulated contractions. However, the novel findings of the present study include 1) PIO2 onset kinetics in response to tetanic contractions can be altered by changing the contraction frequency, with faster kinetics seen as contraction frequency increases, whereas 2) despite the larger metabolic perturbation with increasing contraction frequency, PIO2 offset kinetics following contractions are largely invariant.

Recent work from our laboratory has demonstrated that a doubling of the duration of tetanic contractions resulted in a greater {Delta}PIO2 when contraction frequencies were the same, but the onset kinetics were not different between groups, and an on-off symmetry existed (21). In the present study, increasing contraction frequency resulted in both a greater {Delta}PIO2 and faster MRT, resulting in a significantly faster initial response ({Delta}PIO2/MRT) as frequency increased (see RESULTS). This suggests that frequency of contractions, rather than the magnitude of metabolic perturbation per se, is an important determinant in setting the initial rate of Formula 1O2. As will be discussed, this more rapid activation of mitochondrial respiration at higher contractile frequencies was likely a result of a faster accumulation of the metabolic signals that control the rate of oxidative phosphorylation.

Contraction frequency.   In many whole body studies of pulmonary Formula 1O2 kinetics, bicycle ergometry is the preferred mode of exercise. In general, increasing cycling cadence will increase Formula 1O2 at a given workload (7, 11) because of increases in internal work or the work of overcoming gravitational and inertial forces of the body segments. Barstow et al. (2) showed there was no influence of pedaling frequency (45–90 rpm) on pulmonary Formula 1O2 kinetics, slow-component magnitude, or recovery kinetics, whereas a subsequent report by Pringle et al. (33) showed that increasing pedal frequency (35–115 rpm) at the same relative intensity exercise both decreased the primary component and increased the slow-component magnitude with no changes in time constants or time delays. Two-leg knee extension exercise has been shown to display similar kinetics to cycle exercise as well (24). Using a single-leg extensor model, Ferguson et al. (10) showed that, when contraction frequency increased (60–100 rpm), the Formula 1O2 rose and a corresponding increase in leg blood flow was seen.

Although these whole body studies can vary pedaling (or leg extension) cadence over a wide range, these contractions do not mimic the discrete discontinuous nature of the tetanic contractions in the present study. Pulmonary Formula 1O2 becomes a function of different muscle groups working, changes in muscle blood flow, and pulmonary ventilation. To circumvent many of the issues related to the interpretation of pulmonary Formula 1O2 kinetics during whole body exercise, we chose to study this issue utilizing an intact isolated single fiber preparation. Because the cell is constantly perfused and the external PO2 can be tightly controlled, the issues of blood flow and/or oxygen delivery are not relevant, and the muscle cells are not constrained by oxygen availability (22).

On- and off-kinetics.   In whole body pulmonary Formula 1O2 studies, there is currently no consensus regarding the effects of increased work intensity on Formula 1O2 kinetics. Although several studies (1, 5, 29, 35) have shown that on-kinetics are similar as exercise intensity increases from moderate to heavy exercise, others have shown a slowing of the on-response with increasing work (27, 31), especially during heavy-intensity exercise. One potential reason for the slowed response is the appearance of a significant slow component at workloads above the lactate threshold due to increased fiber recruitment and/or fiber-type differences associated with heavy exercise (see Ref. 12). Regardless, to our knowledge, no whole body studies have reported both an increase in Formula 1O2 amplitude and faster kinetics due to increased metabolic demand as shown in the present study.

Following tetanic contractions in the present study, the MRT for the change in PIO2 from low steady-state levels to resting levels (off-kinetics) was practically identical between conditions (0.5 Hz: 84.0 ± 11.7 s; 0.25 Hz: 79.1 ± 8.4 s; 0.16 Hz: 81.1 ± 8.3 s). This occurred despite the fact that the fall in PIO2 from rest was ~37% greater in the 0.5-Hz condition than in the 0.16-Hz condition and is in agreement with our own previous work with single fibers (21).

As with on-kinetics, previous whole body studies of pulmonary Formula 1O2 have been equivocal regarding the effects of exercise intensity on both the rate of off-kinetics and on-off symmetry. Below the lactate threshold, off-kinetics are usually similar to on-kinetics (26), as mandated by linear first-order control. However, following suprathreshold exercise, off-kinetics are often (25, 27), but not always, faster than corresponding on-kinetics and have even been shown to be slower in some studies (36). As in determining on-kinetics, modeling the effects of the slow component in heavy exercise recovery may affect determination of off-kinetics. However, it has been demonstrated that the magnitude of the slow component per se does not affect recovery kinetics (8). In the present study, the only trial that showed significant amounts of fatigue, determined by a fall in isometric tension, was the high-frequency (0.5 Hz) trial. This suggests that the two lower frequencies were likely below the lactate threshold and that the 0.5-Hz trial was suprathreshold. If true, this would support the idea that the slow component does not affect recovery kinetics.

Metabolic regulation.   Studies of the Formula 1O2 kinetic on- and off-response can provide valuable insights into the regulation of skeletal muscle oxidative phosphorylation. In response to a given step change in ATP demand, skeletal muscle fibers must increase ATP production to match the increased demand. To meet the demand for ATP, skeletal muscle oxidative phosphorylation is activated, and oxygen is utilized. In a closed-loop system, the input signal (ATP hydrolysis) will result in PCr hydrolysis (20) and a resulting change in some effector(s) of oxidative phophorylation (i.e., ADP concentration, Pi, {Delta}GATP, phosphorylation potential). This change in mitochondrial stimulator(s) will elicit an increase in oxidative phosphorylation (output). Experiments using 31P-NMR (6) very elegantly showed that the concentration of PCr changes vary dynamically on a contraction-by-contraction basis and that significant recovery of PCr between contractions occurs, likely due to oxidative phosphorylation. Mahler (28) demonstrated that single fiber Formula 1O2 increases during and decreases after single tetanic contractions in a monoexponential fashion in frog whole muscle and that each contraction has its own amplitude and MRT. In terms of respiratory control, these studies suggest that the signal driving oxidative phosphorylation during a step change in work rate is the summation of many individual (single contraction) changes in metabolite concentrations, based on the frequency and duration of contractions and that Formula 1O2 will respond accordingly. Therefore, in the present study, when the contractions had a larger recovery period between them, the ATP/ADP concentrations were likely buffered temporally by PCr hydrolysis, decreasing the signal(s) to stimulate oxidative phosphorylation and braking the rise in Formula 1O2, resulting in progressively slower kinetics in the 0.25- and 0.16-Hz trials. Conversely, in our previous study (21), although each impulse was doubled in the longer duration condition, the recovery time between contractions was nearly identical. Therefore, the duty cycle, or contraction-to-rest ratio, was different, but the absolute rest period was similar. In the present study, each contraction was of the same duration, but the rate at which each given stimulus occurs was increased, leading to a faster step change to steady state.

At the cessation of contractions, the majority of oxidative metabolism is utilized to restore the energy state of the cell to resting levels. If skeletal muscle is made ischemic via suprasystolic cuffing following exercise, there is no rephosphorylation of PCr, despite the fact that stimulators of oxidative phosphorylation are high (34). PCr recovery rates following stimulation have been demonstrated to be linearly related to oxidative capacity across a citrate synthase range of sixfold (30). Indeed, PCr recovery kinetics are utilized in magnetic resonance spectroscopy studies to estimate oxidative capacity of muscle (3, 20). In the present study, since the oxidative capacity of each cell did not change between conditions, the recovery kinetics were similar between trials.

The present study complements previous work from our laboratory (23) on the importance of creatine kinase (CK) and PCr in both buffering ATP concentrations and controlling respiration. During CK inhibition in isolated single muscle fibers (23), we demonstrated significantly more rapid onset kinetics for the fall in PIO2. Presumably, since PCr is not hydrolyzed with CK inhibition and can therefore not buffer ATP hydrolysis, there is a more rapid increase in free ADP (or another stimulator of oxidative phosphorylation), leading to greater stimulation of oxidative phosphorylation and faster PIO2 on-kinetics. The off-kinetics of PIO2 during recovery were also much faster than the control condition (23), suggesting that the reequilibration of effectors of oxidative phosphorylation occurs much more rapidly when 1) Formula 1O2 kinetics are faster, resulting in a lower oxygen deficit, and 2) the energetic cost of PCr rehydrolysis is reduced.

In summary, increasing the frequency of tetanic contractions of Xenopus single muscle fibers resulted in both a greater decrease in the fall in PIO2 (indicating a greater metabolic disturbance) and faster onset kinetics of this fall, in contrast to the offset kinetics of the recovery of PIO2 being no different between trials. These data suggest that activation of oxidative phosphorylation is modulated in part by the rate of contractions and not only the extent of metabolic perturbation per se, possibly due to buffering of mitochondrial effectors by CK. However, recovery from contractile work is not affected by contraction frequency but appears to depend on intrinsic factors such as oxidative capacity.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants AR-40155 (M. C. Hogan) and 1 F32 AR-48461 (C. A. Kindig). R. A. Howlett and C. A. Kindig were both Parker B. Francis fellows.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. C. Hogan, Dept. of Medicine, MC0623A, Univ. of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0623 (e-mail: mchogan{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.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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