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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
REFERENCES
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The purpose of this study was to examine the
development of fatigue in isolated, single skeletal muscle fibers when
O2 availability was reduced but
not to levels considered rate limiting to mitochondrial respiration. Tetanic force was measured in single living
muscle fibers (n = 6) from
Xenopus laevis while being stimulated
at increasing contraction rates (0.25, 0.33, 0.5, and 1 Hz) in a
sequential manner, with each stimulation frequency lasting 2 min.
Muscle fatigue (determined as 75% of initial maximum force) was
measured during three separate work bouts (with 45 min of rest between) as the perfusate PO2 was switched
between values of 30 ± 1.9, 76 ± 3.0, or 159 Torr in a
blocked-order design. No significant differences were found in the
initial peak tensions between the high-, intermediate-, and
low-PO2 treatments (323 ± 22, 298 ± 27, and 331 ± 24 kPa, respectively). The time to fatigue was
reached significantly sooner (P < 0.05) during the 30-Torr treatment (233 ± 39 s) compared with the
76- (385 ± 62 s) or 159-Torr (416 ± 65 s) treatments. The
calculated critical extracellular PO2
necessary to develop an anoxic core within these fibers was 13 ± 1 Torr, indicating that the extracellular
PO2 of 30 Torr should not have been
rate limiting to mitochondrial respiration. The magnitude of an
unstirred layer (243 ± 64 µm) or an intracellular
O2 diffusion coefficient (0.45 ± 0.04 × 10
5
cm2/s) necessary to develop an
anoxic core under the conditions of the study was unlikely. The earlier
initiation of fatigue during the lowest extracellular
PO2 condition, at physiologically high intracellular PO2 levels,
suggests that muscle performance may be
O2 dependent even when
mitochondrial respiration is not necessarily compromised.
mitochondria; respiration; oxidative phosphorylation; fatigue; oxygen consumption
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IT HAS BEEN SUGGESTED (21) that, during high-intensity work, fatigue occurs when an imbalance develops between the ATP demand of the ATPases and the ATP production by oxidative phosphorylation and substrate-level phosphorylation [glycolysis and phosphocreatine (PCr) hydrolysis]. Whether this ATP supply/demand imbalance is the result of inadequate mitochondrial concentration, substrate limitation (NADH, Pi, ADP) to the working mitochondria, or a result of inadequate availability of O2 as the electron acceptor at the terminal end of oxidative phosphorylation is unclear and likely variable. Although in isolated mitochondria the rate of ADP rephosphorylation only becomes limited when the PO2 is as low as 0.5 Torr (3), ischemic and hypoxic hypoxia have been shown to contribute to an early onset of fatigue in working whole muscle even when the extracellular O2 tension is high (8, 11, 12).
When the concentration of O2 ([O2]) is rate limiting within a working skeletal muscle cell, muscle performance can be directly inhibited by inadequate ADP rephosphorylation. However, our laboratory has demonstrated that modulation of oxidative phosphorylation substrates may occur in whole muscle at similar rates of respiration when tissue oxygenation is altered (6, 8, 12, 13). These changes may have subsequently affected muscle function, leading to an earlier onset of fatigue even though the [O2] was not limiting to oxidative phosphorylation. However, blood flow and fiber type heterogeneity in whole muscle experiments make an exact determination of a specific limitation threshold difficult. Therefore, the extracellular (PO2 extra) and intracellular PO2 (PO2 intra) at which single muscle fibers become compromised, and performance attenuated, are unknown.
In the present study, we used an isolated, working single skeletal muscle cell model to avoid some of these confounding factors associated with whole muscle experiments. PO2 extra was homogeneous and easily determined, and the mitochondria respired in their normal environment. The purpose of the present experiments was to examine single muscle fiber performance at three extracellular O2 tensions that were well above that calculated to be rate limiting to mitochondrial respiration.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Adult female Xenopus laevis were doubly pithed and decapitated. Lumbrical muscles were removed, and single living muscle fibers (n = 6) were microdissected from the muscle. After isolation, myocytes were fiber typed according to cross-sectional area and appearance under dark-field illumination (20). Platinum clips were attached to the tendons, and the fibers were mounted in a glass chamber and continually perfused with Ringer solution (in mM: 112 NaCl, 1.87 KCl, 0.82 CaCl2, 2.38 NaHCO3, 0.07 NaH2PO4) at 20°C and 7.0 pH. Before each contraction period, the resting fiber was passively stretched until the force produced by a single tetanic contraction was maximal (Po).
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 (model S48, Grass Instruments, Quincy, MA) stimulator. Force development was measured with a 5-g force transducer system (model 400A, Aurora Scientific, Aurora, Ontario) and is reported in newtons and kilopascals (kPa = kN/m2). Waveforms were recorded and measured on a Gould flatbed chart recorder (model 220, Gould, Cleveland, OH).
Experimental protocol. Each fiber had its rate of fatigue development measured during three separate work bouts (with 45 min of rest between) with the perfusate PO2 being switched between values of 30 ± 2, 76 ± 3, or 159 Torr in a blocked-order design, which incorporated each possible order of oxygenation. Fibers were stimulated for each of the three work bouts at increasing contraction rates (0.25, 0.33, 0.5, and 1 Hz) in a sequential manner with each stimulation frequency lasting 2 min. Electrical stimulation was terminated when force fell to 50-60% of maximal. Low-PO2 Ringer was generated by N2 aeration and checked with a Clark-style O2 electrode to ensure proper deoxygenation. The PO2 of the Ringer solution in the chamber was monitored with a Clark-style electrode (Diamond General, Ann Arbor, MI) placed adjacent to the working fiber. Individual peak tensions were compared with the highest peak tension within that run (Po). Fatigue was determined as the time point at which the development of force (P) had declined to 75% of the initial maximum tension (P/Po = 0.75).
Calculations.
The relationship between the diffusion of
O2 and its consumption
(
O2) in a muscle fiber that
does not contain myoglobin is described by the Hill equation (7)
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(1) |
O2
is the O2 diffusion coefficient,
the cross-sectional area is the diffusion path length for
O2 (dependent on the radius of the
cell), and
PO2 intra
is the PO2 at the center of the cell.
The Hill equation assumes a uniform distribution of
O2 surrounding a cylindrical
muscle fiber and an absence of any unstirred layers of medium. This
equation can also be used, for a particular
O2, to calculate any
PO2 intra
for any given PO2 extra.
Equation 1 has been extended to
calculate the threshold for O2
limitation
(PO2 critical)
in single muscle fibers (4) by assuming that oxidative phosphorylation
is limited when an anoxic core develops in the center of the cell at
maximal rates of respiration. This threshold is represented by
PO2 extra
when
PO2 intra
is 0 Torr at the highest rate of
O2
(O2 max). This is
summarized by the following equation
|
(2) |
5
cm2/s for
O2
(16) and O2 max
values (average = 0.06 nmol
O2 · mm3 · s1)
for similar Xenopus single fibers
working maximally were used (10). Cross-sectional area was determined
by measuring and averaging the three largest and smallest diameters
with an optical reticle. If muscle performance was compromised under
PO2 extra
conditions not calculated to induce any intracellular anoxic core,
Eq. 2 could be used to calculate the
different
O2
necessary to account for the formation of an anoxic core.
The existence of unstirred layers could also account for a higher than
predicted rate-limiting
PO2 extra
and can be calculated from the following equation (9)
|
(3) |
PO2 is the
PO2 gradient, and
Ke and
Kt are the Krogh coefficients for
extracellular fluid (2.9 × 106 nmol
O2 · mm1 · s1 · mmHg1)
and muscle tissue (2.3 × 106
O2 · mm1 · s1 · mmHg1),
respectively (15, 16).
Statistics. Two-way repeated-measures analysis of variance was used for the statistical analysis. In all analyses, the 0.05 level of significance was used.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The PO2 was maintained at 30 ± 2 Torr during the duration of the low-PO2 fatigue run, 76 ± 3 Torr during the intermediate, and 159 Torr during the high.
No significant differences were found in the initial peak tensions
(Po) between the high- (2.65 ± 0.6 × 103 N = 323 ± 22 kPa), intermediate- (2.44 ± 0.7 × 103 N = 298 ± 27 kPa), and low-PO2 (2.71 ± 0.6 × 103 N = 331 ± 24 kPa) treatments.
Figure 1 compares the time to fatigue for
the low-, intermediate-, and high-PO2
treatments. Fatigue (P/Po = 0.75) was reached significantly sooner
(P < 0.05) during the
low-PO2 treatment (233 ± 39 s)
than during both the intermediate- (385 ± 62 s) and the
high-PO2 treatment (416 ± 65 s).
No significant difference in time to fatigue was found between the
intermediate- and high-PO2
treatments. The large SE for each PO2 condition was a result of differences in fatigability among the fibers.
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The mean cross-sectional area for these single skeletal muscle fibers
was 8 ± 1 × 103
mm2. Fibers were of type I (fast
twitch: n = 3) and type II
(intermediate: n = 3). With the use of the Hill
equation (Eq. 1),
O2
(16) for single amphibian muscle fibers, and previously published mean values for O2 max
corresponding to fiber type (10), the mean core
PO2 intra
was 17 ± 1 Torr at a
PO2 extra
of 30 Torr in these maximally contracting muscle fibers. By using
Eq. 2, the calculated extracellular
PO2 critical
for these fibers was 13 ± 1 Torr. Because it appears that the level
of oxygenation was not rate limiting, yet force production was
compromised, Eq. 2 was used to
calculate an
O2
in the cell cytoplasm (0.45 ± 0.04 × 105
cm2/s) that would have been
necessary to produce an anoxic core at a
PO2 extra
of 30 Torr. Equation 3 was used to
calculate an unstirred layer of medium (242 ± 64 µm), which would
account for a rate-limiting PO2 extra
of 30 Torr.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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These results demonstrated that isolated muscle cells fatigue sooner during high-intensity work at a PO2 extra of 30 Torr, compared with either 76 or 159 Torr, even though the calculated intracellular O2 availability was always higher than that necessary to inhibit the maximal rate of mitochondrial respiration.
Direct effects of O2 limitation. The absence of O2 as the terminal electron acceptor in mitochondrial electron transport will halt oxidative phosphorylation, driving the cell to substrate-level phosphorylation (PCr hydrolysis and anaerobic glycolysis). Work can only be maintained transiently once this occurs, and, in this respect, an O2 limitation would be directly work inhibiting. Studies using isolated mitochondria have provided evidence that a PO2 of 0.5 Torr is necessary to limit isolated mitochondrial oxidative capacity (3). The possibility exists, however, that isolated mitochondria function differently than when in an intact cellular environment. It has been shown that mitochondria form an interconnected tubular network within the cell (1, 17), and it is possible that the isolation method disrupts this interaction, compromising mitochondrial function (19). In addition, it is possible that the in vivo PO2 intra that is rate limiting for maximal respiration is higher than in isolated mitochondrial preparations. The intact, single skeletal muscle fiber model used in the present investigation provides a cellular system composed of an intact intracellular mitochondrial matrix surrounded by an extracellular medium with an O2 tension homogeneous and easily quantifiable. Because these fibers lack myoglobin, O2 diffusion into the cell can be accurately calculated during the duration of the experiments.
In single fibers, the level of extracellular oxygenation necessary to reduce O2 tension at the mitochondria to predicted rate-limiting levels (PO2 critical) can be calculated from an extension of the Hill equation (Eq. 2). This calculation is dependent on theO2 max of the cell, the path length of the diffusion of
O2 into the cell, and a diffusion
constant of O2 through tissue
(O2).
In the Hill model of O2 diffusion
into muscle, the distribution of
O2 surrounding the cell is
homogenous and diffuses radially inward along the concentration
gradient developed from the working mitochondria. When
PO2 critical
is reached during maximal rates of respiration, the supply of
O2 to mitochondria is reduced to a
rate-limiting level and the phosphorylation of ADP cannot keep pace
with the demand of the ATPases, thus compromising cell performance. By using an O2 diffusion constant
calculated by Mahler et al.
(O2 = 1.011 × 105 cm2/s) (16) and
published values of
O2 max of single fibers
similar to those used in the present study (10), the mean calculated value for
PO2 extra
that would be necessary to develop an anoxic core within the maximally
working single Xenopus fibers in the present study was 13 Torr. The results of this study indicate that
force production became limited at a significantly higher PO2 extra.
If the reduction in force were due to an insufficient
O2 supply, the following
explanations for a higher than predicted rate-limiting PO2 extra
would be possible: 1) the
O2
in cytoplasm is inaccurate; 2) even
in a well-stirred or well-perfused system an unstirred layer exists in
the surrounding medium adjacent to the cell;
3) the
PO2 intra
that inhibits the maximal rate of mitochondrial respiration in vivo is
significantly higher than that in isolated mitochondrial preparations;
and 4) performance of the cell
becomes limited before any true anoxic core develops.
The diffusion coefficient presented by Mahler et al. (16) has been
considered the most practical for single skeletal muscle fiber
diffusion considerations. It was developed from studies using frog
tissue at temperatures similar to our preparation. If we assume that
there is a definite, direct O2
limitation at a
PO2 extra
of 30 Torr in the present study, and that the maximal rate of
mitochondrial respiration was similar to published values, it is
possible to extrapolate a diffusion coefficient by using Eq. 2. The diffusion coefficient
calculated is 0.45 × 105
cm2/s, which is a value
significantly lower than related published values (see Ref. 2) and
thereby unlikely.
It is apparent from the Hill equation (Eq. 1) that a strong relationship exists between the
diffusion rate and the path length for
O2 diffusion into the cell. A
higher rate-limiting
PO2 extra than predicted could be accounted for by the magnitude of unstirred layers of medium surrounding the cell. The effect of an unstirred layer
would be an increase in the path length for
O2 diffusion. Equation 3 was used to calculate the
unstirred layer necessary to preserve Mahler's diffusion coefficient
and induce an anoxic core under the experimental conditions of the
present study. This calculated, unstirred layer value would be 243 µm, significantly larger than what is presently believed to be the
thickness of the unstirred layer surrounding a cell (2) and quite
unlikely, considering that these cells were constantly perfused and contracting.
Another possibility is that the
O2-dependent initiation of an
earlier fatigue development at a
PO2 extra
of 30 Torr may have been the result of mitochondrial respiration
inhibition at a higher PO2 than that
found in isolated mitochondrial models. At a
PO2 extra
of 30 Torr, the calculated PO2 at
mitochondria in the center of the cell was 17 Torr, well above the
rate-limiting PO2 of 0.5 Torr in
isolated in vitro mitochondrial models (3). In support of a higher
inhibiting PO2 in in vivo mitochondrial preparations than in isolated mitochondrial models, it
was previously shown (10) that
O2 max of
Xenopus single fibers began to be
significantly reduced at a
PO2 extra
of 90 Torr. At this time, whether the rate-limiting
PO2 for the maximum mitochondrial
respiration in vivo is different than that in isolated mitochondrial
preparations is unknown.
The final possible explanation for the attenuation of force by an
O2 level higher than
PO2 critical
is that an anoxic core failed to develop and that the cell was not
compromised directly by O2
availability. In this case, an alternate cellular mechanism resulting
from the reduced
PO2 extra
might have been initiated, independent of any rate limitation of
oxidative phosphorylation.
Indirect effects of reduced O2 availability. The amount of O2 utilized by the cell is described by Fick's law
|
(4) |
O2, the diffusive capacity of
O2
(O2),
and
PO2 intra
and
PO2 extra.
Reducing PO2 intra
provides the only means to increase the
O2 flux into the cell, as
PO2 extra
and
O2
remain constant. Rumsey et al. (18) and Wilson et al. (23) have
demonstrated, using isolated mitochondria and single-cell models, that
a wide range of O2 values can
influence the metabolic state of the cell. Our laboratory has shown
previously in isolated whole muscle that the concentration of some
intracellular metabolites (H+,
Pi, PCr, and lactate) can be
altered by O2 availability, even when the rate of respiration is not altered (8, 12). In addition, our
laboratory has shown that, in humans, inspiring a reduced fraction of
inspired O2 during exercise
results in an alteration of PCr hydrolysis and intracellular
H+ concentration at steady-state
levels of O2 (6, 13). This intracellular adjustment was accompanied by an earlier onset of fatigue
(13), which we have postulated was a result of mechanisms induced by a
lowered
PO2 intra.
There is evidence that low, but not limiting, levels of
O2 as substrate for oxidative
phosphorylation may drive the cell toward the glycolytic state (8, 12,
14). The association between increased intracellular metabolites and the development of fatigue has been well established, and it is possible that increases in intracellular metabolites directly inhibit
contractility and Ca2+ metabolism
(see Refs. 5, 22).
This relationship between O2
levels and intracellular metabolic intermediates offers the possibility
of an alternate role in the attenuation of force production. It is
possible that the O2 limitation
imposed on the cell in the present study was sufficient to disrupt the
intracellular metabolite concentrations, leading to an attenuation of
force and an earlier onset of fatigue, yet remain high enough to
maintain respiration. If this is correct, it is possible that the
reduction in O2 max
observed previously (10) on reduced
O2 availability was secondary to
an attenuation of force production. This reduction in
O2 max would,
therefore, be caused primarily by an intracellular disruption in
metabolite concentration, inhibiting contractility and decreasing the
ATP demand. Whether the reductions in force production and respiration observed in this and the previous study (10) were a primary effect
because of reduced O2 utilization
or secondary due to metabolic inhibition of force remains to be determined.
In summary, the results of this study indicate that a
PO2 extra
of 30 Torr is sufficient to induce an earlier onset of fatigue in
working, isolated single muscle fibers. This
PO2 extra
is significantly above that predicted necessary to produce an
intracellular O2 tension low
enough to be rate limiting to mitochondria, even at the highest rates
of respiration. This suggests that, in working single skeletal muscle
fibers, force generation may be affected by a
PO2 intra
above that which limits mitochondrial respiration, possibly mediated
through secondary effects of
[O2] on other cellular processes.
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ACKNOWLEDGEMENTS |
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The authors thank Aleksander Popel for significant mathematical contributions to this study.
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FOOTNOTES |
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This research was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant AR-40155.
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 24 September 1998; accepted in final form 1 February 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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