1 Division of Physiology and Metabolism, Department of Nutrition Sciences, 2 Department of Critical and Diagnostic Care, and 3 Department of Human Studies, The University of Alabama at Birmingham, Birmingham, Alabama 35294; and 4 Medical Department, Brookhaven National Laboratory, Upton, New York 11973
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ABSTRACT |
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We used 31P magnetic resonance spectroscopy to measure maximal mitochondrial function in 12 obesity-prone women before and after diet-induced weight reduction and in 12 matched, never-obese, and 7 endurance-trained controls. Mitochondrial function was modeled after maximum-effort plantar flexion from the phosphocreatine recovery time constant (TCPCr), the ADP recovery time constant (TCADP), and the rate of change in PCr during the first 14 s of recovery (OxPhos). Weight reduction was not associated with a significant change in mitochondrial function by TCPCr, TCADP, or OxPhos. Mitochondrial function was not different between postobese and never-obese controls by TCPCr [35.1 ± 2.5 (SE) vs. 34.6 ± 2.5 s], TCADP (22.9 ± 1.8 vs. 21.2 ± 1.8 s), or OxPhos (0.26 ± 0.03 vs. 0.25 ± 0.03 mM ATP/s), postobese vs. never-obese, respectively. However, TCADP was significantly faster (14.5 ± 2.3 s), and OxPhos was significantly higher (0.38 ± 0.04 mM ATP/s) in the endurance-trained group. These results suggest that maximal mitochondrial function is not impaired in normal-weight obesity-prone women relative to their never-obese counterparts but is increased in endurance-trained women.
nuclear magnetic resonance; skeletal muscle; oxidative phosphorylation; endurance training
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INTRODUCTION |
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A NUMBER OF PREVIOUS STUDIES have found low proportions
of slow-twitch, oxidative (type I) fibers (10, 11, 16, 34) and high
proportions of glycolytic, fast-twitch (type IIb) fibers (10, 11, 16)
in the vastus lateralis (10, 11, 16, 34) and rectus abdominus muscles
(6) of individuals with high body fat stores. These studies are
interpreted to imply that skeletal muscle characteristics play a role
in the etiology of obesity because of underlying differences among
fiber types in substrate oxidation capacities, particularly for lipids
(34), i.e., type I fibers are well endowed with mitochondria and have a
high capacity for fatty acid oxidation, whereas type IIb fibers (particularly those that are not adapted by regular exercise) have low
mitochondrial enzyme activity and more readily utilize carbohydrate via
glycolysis for energy supply (7). Recently, Simoneau and Bouchard (27)
reported that low activity of malate dehydrogenase, a marker enzyme for
the tricarboxylic acid (TCA) cycle, was a better determinant of body
fat than fiber type. Preliminary data of Simoneau and colleagues have
also found that low activity of -ketoglutarate dehydrogenase,
another TCA cycle marker, was associated with greater body fat gain
over a 13-yr period (26) and after overfeeding (29). Although these
studies suggest that muscle fiber characteristics may be involved in
obesity pathogenesis, only a few (21, 27) have accounted for the
possibility that these characteristics may reflect physical activity
patterns rather than an inherent muscle metabolic profile that is
predisposing to obesity.
Recently, 31P magnetic resonance spectroscopy
(31P MRS) has emerged as a powerful tool for noninvasively
studying the oxidative metabolism of skeletal muscle during exercise
(9). With use of 31P MRS, mitochondrial function has been
modeled from the recovery time constants of both phosphocreatine (PCr)
and ADP after exercise (1, 2) and from the rate of change of PCr during
the initial 14 s of recovery (5, 18). These methods are thought to
reflect ATP generation from oxidative phosphorylation via the reverse creatine kinase (CK) reaction. Each approach, however, may be detecting
slightly different aspects of mitochondrial function (14), which is
also likely to differ from the biopsy approach of measuring maximal
activity of marker oxidative enzymes (33), i.e., malate dehydrogenase
or -ketoglutarate dehydrogenase.
The intent of this study was to determine 1) whether skeletal muscle maximal mitochondrial function is altered in obese women after weight reduction and 2) whether it is impaired in normal-weight previously obese (postobese) women relative to matched, never-obese controls and endurance-trained controls with a suspected high oxidative capacity. Because the criteria for judging whether subjects perform true maximal effort is highly subjective, a secondary purpose was to determine whether controlled near-maximal exercise produces results equivalent to maximum effort exercise in these populations.
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METHODS |
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Subjects.
Twelve moderately obese, nondiabetic, premenopausal women and 12 never-obese controls participating in a longitudinal investigation of
the role of energy metabolism in the pathogenesis of obesity were
included in the analyses. The moderately obese women were recruited
specifically to have a body mass index (BMI) between 27 and 30 kg/m2 and a positive family history of obesity. These women
were evaluated before (obese) and after diet-induced weight reduction
to normal body weight (postobese) (BMI <25 kg/m2). The
never-obese controls were recruited specifically to group match with
the postobese subjects in terms of premenopausal status, BMI, body
composition, and sedentary lifestyle but did not have a personal or
family history of obesity. In addition, seven premenopausal, recreational endurance athletes were recruited to serve as
endurance-trained controls. The endurance-trained women trained
regularly (5 days/wk) in aerobic sports, including distance running,
cycling, triathalons, and aerobic dance. Many placed regularly at local
competitions either overall or in their age group, but none were
national caliber athletes. None of the women were taking medications
known to affect body composition, insulin sensitivity, or energy metabolism.
Experimental protocol. The obese women participating in the weight-reduction phase were given foods providing 800 kcal/day (22% protein, 14% fat, 64% carbohydrate) for the length of time needed to lose a minimum of 10 kg and achieve a BMI <25 kg/m2. No exercise instructions were provided. For 1 mo before testing, the weight of obese and normal-weight subjects was documented as being stable through twice weekly body-weight measurements. For the 24 women participating in the ongoing longitudinal study, a macronutrient-controlled diet (16% protein, 20% fat, 64% carbohydrate) was provided by the General Clinical Research Center at UAB for the 2 wk preceding testing, with energy level adjusted to ensure weight stability. For the trained women, diet composition was monitored for 2 days before testing by an exchange-system food plan that approximated the macronutrient composition of the controlled diet. For women participating in the longitudinal study, all testing was performed in the follicular phase of the menstrual cycle (within 10 days of the start of menses). For the endurance-trained controls, testing was performed either in the follicular phase or, if the women were taking oral contraceptives, during the 7 days of inert pills, i.e., reflecting the follicular phase. In the women suspected to be anovulatory, progesterone levels were measured before testing to document an anovulatory or follicular state (i.e., progesterone level <2.0 ng).
The experimental protocol involved two exercise sessions, separated byWhole body
O2 max.
Testing was performed in the morning after an overnight fast.
O2 max was determined
by indirect calorimetry on a treadmill by use of a modified Bruce
Protocol to exhaustion. The volumes of O2 and
CO2 were measured continuously by open-circuit spirometry and analyzed using a Sensormedics metabolic measurement cart (model 2900, Yorba Linda, CA). Heart rate was monitored by a Polar Vantage XL
heart rate monitor (Polar Beat, Port Washington, NY). The highest
O2, respiratory exchange
ratio (RER), and heart rate achieved over a 20-s period within the last
2 min of exercise were recorded as
O2 max,
RERmax, and HRmax, respectively. For the test
to be considered an acceptable measurement of physiological
O2 max, two of the
following criteria had to be met: 1) a leveling or plauteauing
of
O2 (defined as an
increase of
O2 of <2
ml · kg
1 · min
1
with increased workload), 2) RER >1.1, and 3) maximum
heart rate within 10 beats of age-predicted maximum (25).
Skeletal muscle mitochondrial function.
1H-magnetic resonance images (MRI) and 31P MRS
were collected on a 4.1-T whole body imaging and spectroscopy system,
as previously described (14). Subjects were requested to fast and
abstain from caffeinated beverages for 6 h and from exercise for
24 h before testing. Mitochondrial function was calculated from the recovery of PCr and ADP after each 90-s isometric plantar flexion exercise, which primarily worked the gastrocnemius and soleus muscle
groups. The exercise bench and force collection devices were similar to
previously described devices (5, 18).
Calculations. Mitochondrial function was estimated from several previously described models: 1) time constant of PCr recovery (TCPCr), 2) time constant of ADP recovery (TCADP) (1, 2), and 3) ATP production rate from oxidative phosphorylation (OxPhos) (5, 18). Specifically, TCPCr and TCADP were determined by fitting the recovery of each of these metabolites to a monoexponential curve by use of Sigma Plot (Jandel Scientific, San Rafael, CA). OxPhos was calculated using the model of Boska (10) and Newcomer and Boska (5, 18), which obtains ATP production rates from the rate of change of PCr during the first 14 s after exercise. The reproducibility of these measurements is better than 6% for TCPCr and TCADP and better than 10% for OxPhos (14). pH was calculated from the chemical shift difference between the Pi peak and the PCr peak (2, 32). The concentration of ADP was calculated from the equilibrium equation of the CK reaction with the assumption of an unchanged total creatine pool (PCr and creatine), an equilibrium constant, Keq = 1.66 × 109 (15), and a 15% unphosphorylated creatine pool at rest (5).
Statistics.
Changes in mitochondrial function by the three methods after the
near-maximum and maximum exercises between the obese and postobese
states were tested using a randomized block factorial design; blocking
on subjects, the factors were group (obese and postobese), methods
(TCPCr, TCADP, and OxPhos), and force levels (70% MVC and 100% MVC). Differences in mitochondrial function after
the near-maximum and maximum exercises between the postobese and
control groups by the different methods were tested using a split-plot
repeated-measures design; blocking the split plot on subjects by group
(postobese, never-obese, and endurance-trained), the factors were
methods (TCPCr, TCADP, and OxPhos) and
force-levels (70 and 100% MVC). These designs allowed for the testing
of main and interactive effects of all independent variables (markers of mitochondrial function at 70 and 100% MVC in the different groups)
simultaneously. For descriptive variables, differences between obese
and postobese subjects were tested using a paired t-test.
Differences among postobese, never-obese, and endurance-trained groups
were tested using simple analysis of variance (ANOVA). Where
appropriate, post hoc tests were conducted using least squares means
and adjusted using Bonferroni corrections for multiple comparisons. Comparisons between never-obese and endurance-trained controls were not
performed, because it was set a priori to compare postobese women with
never-obese controls and postobese women with endurance-trained controls. The relationships among variables were analyzed using Pearson
correlation coefficients. For the randomized block factorial design and
the split-plot repeated-measures design, statistical significance was
accepted using a one-tail, 5% level of significance. For all other
tests, was also set at 0.05. All data presented in this paper are
means ± SE.
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RESULTS |
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Physical characteristics,
O2 max , and
habitual physical activity.
The characteristics,
O2 max, and habitual
physical activity of the 12 obese women before and after diet-induced
weight reduction and those of the control groups are shown in Table
1. Obese women lost 11.1 ± 0.9 kg over a
4- to 7-mo period, resulting in significant decreases in BMI, fat mass,
and percentage body fat. Among the normal-weight groups (postobese,
never-obese, and endurance-trained), there was a significant group
interaction for age, body mass, BMI, fat mass, and percentage body fat,
an interaction that was primarily explained by the endurance-trained
group. Postobese and never-obese subjects were closely matched for all
characteristics except age, with never-obese controls being
significantly younger than both postobese and endurance-trained
controls. Trained controls had lower body mass, BMI, fat mass, and
percentage body fat than postobese women.
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Isometric plantar flexion exercises.
Figure 1 illustrates a typical
31P MRS stacked plot of spectra obtained during rest,
exercise, and recovery for the 70 and 100% MVC plantar flexion
exercises. The spectra are typical of all subgroups and illustrate the
fall in PCr and rise in Pi that occur during a 90-s
isometric contraction and the subsequent recovery of these metabolites
after exercise. The ratio of PCr to Pi is reflective of the
cellular bioenergetic state (22). The spectra also show that ATP
concentration, determined from the area of the - and
-ATP peaks,
does not change during exercise. The
-ATP peak could not be obtained
using the adiabatic pulse used on our 4.1-T system because of power and
hardware limitations.
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Effect of weight reduction on mitochondrial function.
The effect of weight reduction on the three markers of mitochondrial
function was analyzed using a group (obese and postobese)-by-method approach, because there was no significant effect of
group-by-force-by-method (P = 0.66), group-by-force (P = 0.33), or force (P = 0.52). Thus the data for the
70 and 100% MVC exercises were collapsed in the model. Table
3 summarizes the mitochondrial function
markers after the 70 and 100% isometric plantar flexion exercises and the collapsed means. No significant change in mitochondrial function with weight reduction was found by any of the markers (Table 3, Fig.
3). It is interesting to
note, however, that the data appear skewed in the obese state toward a
reduced mitochondrial function (higher time constants) by all markers
(change in the median compared with the mean; Fig. 3). After weight
reduction, the median shifts toward an improved mitochondrial function.
By all markers, mitochondrial function was well correlated within
subjects before and after weight reduction (Table
4).
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Effect of obesity predisposition and training on mitochondrial function. The effect of group (postobese, never-obese, and endurance-trained) on the markers of mitochondrial function was analyzed using a group-by-method approach, because there was no significant effect of group-by-force-by-method (P = 0.45), group-by-force (P = 0.36), or force (P = 0.98). Thus the data for the 70 and 100% MVC exercises were collapsed as they were in the obese and postobese comparisons. Table 3 summarizes the mitochondrial function markers after the 70 and 100% isometric plantar flexion exercises and the collapsed means. There was no significant difference in mitochondrial function between the postobese and never-obese controls by any method (Table 3, Fig. 3). In fact, the means and medians were similar for all markers. In contrast, TCADP was significantly faster and OxPhos was significantly higher in the endurance-trained controls compared with the postobese subjects (P < 0.05) (Fig. 3). TCPCr was also considerably faster in the endurance-trained compared with the postobese group (Fig. 2), but the 1.6% overlap in the confidence intervals indicated lack of statistical significance.
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DISCUSSION |
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It has been suggested that a low substrate oxidative capacity of skeletal muscle, measured by histochemical or enzymatic analysis, plays a role in the etiology of obesity (27, 34). In the current analysis, we used 31P MRS to measure maximal oxidative phosphorylation, i.e., mitochondrial function, in the calf muscle of obesity-prone women before and after diet-induced weight reduction and in never-obese, body composition-matched controls and endurance-trained controls. Our main findings were that mitochondrial function was not significantly altered by diet-induced weight reduction and was not reduced in normal-weight, postobese women relative to matched, never-obese controls. We also found that a controlled near-maximal exercise, which is not dependent on subjective judgment by an investigator (as to the subjects' exercise compliance and motivation), may be used in lieu of maximal exercise to estimate maximal mitochondrial function.
Very little is known concerning the effect of weight reduction on mitochondrial function. Several previous studies have reported that fiber-type composition (20, 31) or citrate synthase activity (31) of the vastus lateralis muscle is not altered with a 12-wk energy-restrictive diet, but that citrate synthase activity is increased by ~35% when exercise is included in the weight-reduction program (31). In the current study, we did not detect a significant difference in maximal mitochondrial function by TCPCr, TCADP, and OxPhos but noted a shift in the median values of these markers toward improved mitochondrial function (Fig. 3). Interestingly, in a larger subset of 18 subjects who performed only 45 and 70% MVC exercises, mitochondrial function, measured by TCPCr and TCADP but not OxPhos, was found to improve after weight reduction (unpublished observations). This suggests that at least some aspects of mitochondrial function may be improved with weight reduction, possibly due to a spontaneous increase in physical activity during/after weight loss or an improved insulin sensitivity, both of which have been noted in our subjects with this degree of weight loss (unpublished observations). Although all of our obese subjects were nondiabetics, interesting work by Sato et al. (24) in working heart muscle has suggested that insulin plays a critical role in maintaining mitochondrial efficiency (work performed per mole of O2 consumed).
The absence of a difference in skeletal muscle oxidative capacity
between postobese and fitness-matched, never-obese subjects is in
contrast with the hypothesis that a low substrate oxidative capacity of
skeletal muscle is involved in the pathogenesis of obesity. A number of
studies have reported associations between increased adiposity and
decreased proportions of type I (11, 16, 34) and increased proportions
of type IIb (10, 11, 16) muscle fibers. These findings have been
interpreted to imply that obesity-prone individuals have a different
skeletal muscle substrate oxidation profile, particularly for lipid.
Previous studies, however, have not controlled for subjects' physical
fitness levels and have focused most often on male (11, 16, 34) or
mixed-gender populations (6, 10). The few studies that have analyzed
this relationship exclusively in women have not found a relationship
between adiposity and muscle fiber composition (12, 27), which
indirectly supports our findings. Our results, however, are in line
with those of Simoneau and Bouchard (27) and Raben et al. (21).
Simoneau and Bouchard have reported that a low activity of malate
dehydrogenase was related to body fatness in men but not in women when
aerobic fitness
(O2 max) was
taken into account. Raben et al. recently reported that the apparently lower activity of citrate synthase and
-hydroxyacyl-CoA
dehydrogenase in postobese compared with never-obese women not
initially matched for physical fitness, disappeared after differences
in
O2 max had been
accounted for.
Because of the novelty of 31P MRS in obesity research, we maximized the potential for detecting differences between postobese and never-obese subjects by measuring oxidative phosphorylation by use of three reliable markers of mitochondrial function (14). The assumptions underlying these markers have recently been reviewed (14) and are described in the literature (1, 2, 5). Briefly, TCPCr is found to be very sensitive to differences in intramuscular pH, TCADP is proposed to be a better pH-independent marker of mitochondrial function (1, 2), and OxPhos is thought to minimize the contribution of blood reflow to measurement of mitochondrial function (5). We also included a control group with a suspected high skeletal muscle oxidative capacity (17), i.e., the endurance-trained group, to ensure that these MRS markers were sensitive enough to detect expected differences in mitochondrial function. As illustrated in Fig. 3, the endurance-trained group had faster TCPCr , significantly faster TCADP, and significantly higher OxPhos than the postobese group, all of which reflect an enhanced oxidative phosphorylation. An increase in mitochondrial oxidative capacity is expected (19) because of an increase in the maximal activity of oxidative enzymes (7) involved in mitochondrial metabolic flux. In contrast, the postobese group had oxidative capacity measurements that were strikingly similar to those of their aerobic fitness-matched, never-obese counterparts. The range of oxidative metabolism detected in our nonathletic women (~threefold for both TCPCr and TCADP and ~sixfold for OxPhos) is also similar to the four- to fivefold range in TCA cycle enzymes reported for nonathletes (27, 37).
It is worth clarifying that 31P MRS detects differences in oxidative metabolism that are not specific to the source of NADH (5) and are more reflective of metabolic flux than a rate-limiting enzyme control of metabolism (8, 33). Reducing equivalents that enter oxidative phosphorylation can be derived from glucose, muscle glycogen, fatty acid, or amino acid metabolism. Although this is in contrast to analysis of maximal activity of marker enzymes in substrate-specific pathways (i.e., glycolysis or fatty acid oxidation), it is in some respects similar to analysis of TCA cycle enzymes, which also are not specific to the initial source of substrate (acetyl-CoA). Acetyl-CoA can be delivered from glucose, fatty acid, or amino acid metabolism. Several recent studies have suggested (34) that obesity-prone men and women have a reduced ability to oxidize fat relative to carbohydrate (3, 13, 23), an inability that may increase risk for subsequent body weight gain (36). The specific mechanism for the purported reduced capacity to oxidize fatty acids and the mechanism whereby it would be expected to lead to obesity are not known. Even the relation between adiposity and fiber type is not strongly suggestive of a reduced capacity to oxidize lipid, because only weak correlations have been reported between lipid oxidation enzymes and fiber type in sedentary men and women (28). Recent advances in understanding the control of metabolic pathways, however, have not given support to the concept that control of metabolic flux can be interpreted in terms of rate-limiting or marker enzyme steps in a given pathway (8, 33). The present study addresses overall differences in oxidative capacity (i.e., metabolic flux) and does not support the hypothesis that obesity-prone women have a reduced capacity to oxidize macronutrients in favor of storage.
A secondary objective of this study was to determine whether a
controlled, near-maximal exercise produces results similar to a
maximum-effort exercise. A recent analysis from our laboratory has
found that, after the 100% MVC, TCPCr, TCADP,
and Oxphos are correlated with whole body
O2 max across a range
of fitness levels and that this correlation is equally strong when
mitochondrial function is determined after the 70% MVC exercise (14).
In addition, OxPhos was the only method that detected a significant
increase in mitochondrial function between the 70 and 100% MVC
exercises (14). TCPCr was actually prolonged after the
100% MVC exercise because of interference by decreasing pH (as
discussed earlier). In the present study, this same pattern was noted
(see Table 3). We also found that data from the near-maximum and
maximum exercises could be collapsed in a complex ANOVA model, because
the interaction of force was not statistically significant. These
findings are of interest because achievement of a true maximum effort
is dependent on subject motivation and, in our experience, is more
difficult in sedentary women not accustomed to performing full-effort
exercises. In contrast, the 70% MVC, near-maximal exercise dictates
that a certain force level be held steady throughout the 90-s exercise and is, therefore, less dependent on investigator interpretation of the
subject's motivational state. These results, in combination with our
previous analysis, suggest that a near-maximal exercise could be used
in lieu of a maximal exercise to estimate the maximal oxidative
phosphorylation of working muscle.
In conclusion, our results indicate that oxidative phosphorylation measured by 31P MRS markers of mitochondrial function is neither significantly altered by diet-induced weight reduction nor impaired in normal-weight postobese women relative to never-obese controls with similar levels of physical fitness. As expected, our data also verify that oxidative phosphorylation is elevated in endurance-trained women, but they suggest that TCPCr may not be as sensitive as TCADP and OxPhos at detecting these expected differences in small numbers of subjects. Finally, the findings do not support the hypothesis that an inherently low skeletal muscle oxidative capacity is involved in the etiology of obesity in women. They suggest, instead, that a low oxidative capacity of skeletal muscle is more likely reflective of differences in physical activity patterns.
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ACKNOWLEDGEMENTS |
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We thank Betty Darnel and the Metabolic Kitchen staff, University of Alabama at Birmingham General Clinical Research Center, for assistance on this project, and Nestle Food Co. (Solon, OH) for kindly providing the Stouffer's Lean Cuisine entrees used on the macronutrient-controlled diets. Most important, we thank the volunteers.
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FOOTNOTES |
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This research was supported in part by grants from the National Institutes of Health (NIH) (RO1 DK-49779 and RO1 DK-51684), the National Center for Research Resources, NIH (NCRR RR 11811), the University of Alabama at Birmingham General Clinical Research Center (MO1-RR-32), and the University of Alabama at Birmingham University-Wide Obesity Nutrition Research Center.
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: D. E. Larson-Meyer, Division of Physiology and Metabolism, Department of Nutrition Sciences, 1675 University Blvd., The University of Alabama at Birmingham, Birmingham, AL 35205.
Received 31 March 1999; accepted in final form 15 September 1999.
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