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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:B801-B808 (2004)
© 2004 The Gerontological Society of America

Oxygen Consumption During Maximal Exercise in Fischer 344 x Brown Norway F1 Hybrid Rats

I. Mark Olfert, Jamal Balouch and Odile Mathieu-Costello

Department of Medicine, Division of Physiology, University of California, San Diego.

Address correspondence to Mark Olfert, PhD, Department of Medicine 0623A, University of California–San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0623. E-mail: molfert{at}ucsd.edu


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
We characterized O2 consumption (VO2) during treadmill exercise in 12-, 24-, and 35-month-old Fischer 344 x Brown Norway F1 hybrid (F344BNF1) rats. When accounting for differences in body mass (Mb), VO2peak decreased by 10% and 33% in 24- and 35-month-old rats, respectively, compared with rats at 12 months (analysis of covariance, p <.01). O2 cost per unit work at VO2peak (i.e., VO2peak/work) was greater in 35-month-old rats compared with 12- and 24-month-old rats (p <.001). During submaximal exercise, the O2 cost was greater in 24- and 35-month-old than 12-month-old rats (p <.01). Analysis of covariance revealed similar patterns irrespective of differences in Mb or lean Mb as covariates. The underlying mechanism responsible for increasing O2 consumption in aged F344BNF1 rats during exercise, although partly explained by mechanical inefficiencies of locomotion, still remains to be determined.

Aging is associated with decreased muscle strength, endurance, and physical performance, which is evidenced by a gradual decline of maximal or peak aerobic capacity (VO2peak). The rat, owing to its relatively short life span (2–3 years), is a widely used animal model to study the effects of aging. Historically, the Fischer 344 (F344) rat strain has served as a major mammalian model for aging studies. However, during the past decade, the appropriateness of using a single genetically homogenous inbred rat strain has been called into question (1). Adding to this, the genetic predisposition of F344 rats to succumb to severe glomerulonephropathy, granular cell leukemia, and interstitial cell tumors of the testis also gives rise to the concern in the ability to separate the biology of disease from the biology of aging (2–4).

The development of the Fischer 344 x Brown Norway F1 (F344BNF1) hybrid rat, although also a genetically homogenous strain, has produced a more robust rat strain, which, unlike the F344 strain (which results in 50% mortality at ~25 months), attains a 50% mortality at ~33 months (5,6). This greater longevity may be due to the fact that, at the same absolute age, F344BNF1 rats have a fewer number of pathologies than F344 rats (5–8). However, it is interesting to note that the differences in the number of pathologies between the two strains are significantly lessened when comparison is made at the same relative ages (5–8), thus calling into question whether the greater longevity of F344BNF1 rats is in fact due to fewer pathologies. Nevertheless, the longer life span of F344BNF1 hybrid rats has resulted in much older rats (up to 38 months of age or more) being available for gerontological studies.

Many studies have reported the effect of increasing age on whole-body O2 consumption (VO2), but the majority of these studies have been limited to rats up to 24 months of age (9–12), and, as yet, there is no whole-body VO2 data in very old rats > 30 months of age. There is also no data yet available on whole-body VO2 or VO2peak in the F344BNF1 hybrid rat strain. Given that the variability in VO2 is well documented among rat strains (13), and the lack of whole-body VO2 data in rats > 30 months of age, we sought to characterize the whole-body and peak VO2 in 12-, 24-, and 35-month-old F344BNF1 rats. Although one advantage of using an inbred or F1 hybrid rat strain is the elimination of genetic variability, significant phenotypic variability is still possible even when an inbred strain is maintained under uniform environmental conditions (2). Therefore, we also sought to determine whether significant phenotypic variability would be found in VO2 of F344BNF1 rats.

We expected that VO2peak would be the lowest in the oldest (35 months) and highest in 12-month-old F344BNF1 rats, and hypothesized that the rate of decline in VO2peak would remain constant with advancing age. Based on data found in other rat strains (9,13), we also hypothesized that O2 consumption during exercise (i.e., O2 cost at any given level of work) would decrease with age.


   MATERIALS AND METHODS
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
This study was approved by the University of California, San Diego, Animal Subjects Committee, and conducted in pathogen-free facilities that are accredited by the American Association of Accreditation of Laboratory Animal Care.

We obtained 12-month-old (n = 20), 24-month-old (n = 20), and 35-month-old (n = 20) male F344BNF1 rats, which had been born and bred at the National Institute on Aging colony at Harlan Industries (Indianapolis, IN). The rats arrived at the University of California, San Diego, on two separate occasions, several months apart. The first delivery included a total of 45 animals (n = 15 for each age group), while the second delivery was composed of a total of 15 rats (n = 5 for each age group). All rats were confined to standard size rodent cages (2–3 rats of the same age per cage) and maintained on a 12:12 day/night cycle in the same room. Rats had unrestricted access to standard rat chow (Harlan Teklad 8604) and untreated tap water. Total time spent at the laboratory was approximately 2 to 3 weeks for all rats.

Exercise Testing and Protocol
Assessment of VO2 was made using a specially designed single-lane treadmill enclosed in an air-tight Plexiglas metabolic chamber (10.5 cm x 16.5 cm x 42 cm) equipped with two inlets for inspired and expired gas. Prior to testing, animals were weighed (Ohaus Scale Corp., Florham, NJ) and familiarized to the treadmill (at a slow speed, usually <5 meters/minute [m/min] and 0° incline for a minimum of 5–10 minutes) at least 1 day prior to testing. To encourage and keep rats running, the treadmill was equipped with an electrical shock grid at the rear of the treadmill. The shock grid was set to deliver 0.2 mA, and results in an uncomfortable shock but does not physically harm or injure the rodent. All animals exercised using the same basic protocol with a slight modification for the 35-month-old rats, due to their reduced mobility at high speeds. The exercise protocol and time spent at each work level (i.e., treadmill speed and incline) are shown in Table 1. Each rat was run until exhaustion, which was defined as the point when they were no longer able to maintain a position on the treadmill. Typically, the maximal running speed (with 15° incline) was ~ 23, 14, and 6 m/min for 12-, 24-, and 35-month-old rats, respectively. Of the 35-month-old rats studied, only two achieved a running speed above 8 m/min, while all the younger 12- and 24-month-old rats were able to perform beyond this level of work. All 24- and 35-month-old rats, and the majority of 12-month-old rats, were tested twice on different days. All groups were tested over a 3–4 day period, in a mixed order with respect to age and time of day (i.e., morning vs afternoon).


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  		Table 1. Treadmill Exercise Protocol.

 
Work during exercise was measured as animal body mass (kg) times the vertical distance (Z) traveled on the treadmill (i.e., kg x Z), with Z calculated as sine {theta} x d where {theta} is the degree of inclination and d is the total distance in meters (i.e., d = speed x time at workload) traveled along the incline.

Measurement of O2 Consumption
Ambient air from a compressed gas source was pumped through the metabolic chamber at a rate between 5 and 6 L/min and was measured using a dry gas flowmeter. The accuracy of the flowmeter was initially verified using a calibrated spirometer. Relative humidity, chamber temperature, and outflow O2 and CO2 gas concentrations were continuously measured and digitally recorded (Acqknowledge 3.7.1.; Biopac Systems, Inc., Santa Barbara, CA) from the gas outflow at the rear of the treadmill. At the start of each workload, O2 and CO2 concentration from inflow gas was also sampled and recorded. O2 and CO2 gas concentrations were measured using a mass spectrometer (Perkin-Elmer 1100 MGA, Pomona, CA), which was calibrated using a standard gas concentration. O2 consumption (VO2) and CO2 production (VCO2) were calculated from O2 and CO2 data obtained during steady-state exercise (i.e., during the end of each workload) using the following equation:


{grna-59-08-12-eq1}

where FIO2 and FICO2are the fractions of inspired O2 and CO2, and FEO2 and FECO2 are the fractions of expired O2 and CO2, respectively. The respiratory exchange ratio (RER) was calculated as VCO2/VO2.

Resting VO2 was obtained during 5–10 minutes immediately prior to the start of exercise. Rats were always free to move within the chamber surrounding the treadmill apparatus, and the shock grid (at the rear of the treadmill) remained off during the whole resting period.

Maximal O2 consumption (i.e., VO2max) is typically defined by a plateau in VO2 despite increasing work intensity. Because a VO2 plateau was generally not achieved during maximal exercise in the majority of rats tested, the highest VO2 value obtained (i.e., VO2peak) during exercise was used as VO2max.

Muscle Dissection
Rats were anesthetized with sodium pentobarbital (30–90 mg/kg) and muscles from both left and right hind limbs (i.e., tibialis anterior, extensor digitorum longus, gastrocnemius, soleus, and plantaris) were surgically dissected, weighed, and quickly frozen for histochemical analysis (15). Alternatively, in some rats, muscles were dissected following whole-body perfusion fixation procedure [previously described in (16)] for morphological analysis (17). In both cases, however, individual weights of left and right muscles were averaged to yield a single mean value for each muscle in this study. Incomplete muscle sampling occurred in 2 perfusion-fixed rats in the 24-month age group and therefore they were not included in our analysis. The proportion of fresh to fixed muscle tissue within each age group was essentially identical, with the number of fixed muscles comprising a total of 6, 4, and 6 rats (of the 20, 18, and 20 total rats) in the 12-, 24-, and 35-month age groups, respectively. Thus, whereas fixation tended to lower muscle mass, it did not affect the outcome of intergroup comparisons.

Lean Body Mass
Body fat percentage (BF%) and lean Mb (LBM) was determined using dual-energy X-ray absorptiometry (DEXA). DEXA has been well described in the literature (18–20) and provides noninvasive quantification method for both regional and whole-body composition, as well as bone mineral content. Briefly, the measurement is based on the differential attenuation of low (70 keV) and high (140 keV) energy X-rays, which occur in proportion to tissue density, i.e., bone mass attenuates the energy beam more than soft tissue (lean and fat mass), and lean mass attenuates it more than fat mass. This, in conjunction with a tissue calibration phantom, permits the partitioning of soft tissues into fat mass (primarily adipose tissue) and lean mass (comprising skeletal muscle, organs, tendons, cartilage, blood, and body water).

Lean Mb was only determined in a subset of rats from each age group (n = 5 per age group). These rats were euthanized (intraperitoneal injection of 120 mg/kg sodium pentobarbital) and placed on the DEXA scanner (QDR-2000; Hologic, Inc., Waltham, MA) in a dorsal recumbent position. Determination of fat, lean, and total body mass was made using the Rat Whole Body software package (V7.0-Rev. C; Hologic, Inc.). The DEXA-measured Mb was found to be in close agreement (coefficient of variation = 0.5%) with the Mb obtained using a separate calibrated electronic scale (CT6000; Ohaus Corp., Florham, NJ). Bland-Altman analysis comparing the differences in Mb between these two measurements revealed a slight tendency for DEXA Mb to overestimate Mb by an average of 3 grams (data not shown), a difference so small (<0.7%) in the range of Mb of our animals that it is biologically insignificant.

Statistical Analysis
Data are expressed as mean ± SE (standard error) unless otherwise indicated. Analysis of covariance (ANCOVA) was used to determine significant relationships between VO2 and age with covariates of either Mb or lean Mb, using commercially available statistical and data analysis software (NCSS 2004, Kaysville, Utah; www.ncss.com). Analysis of variance (ANOVA; NCSS 2004) was used to determine significant differences in body and muscle masses, % body fat, RER, maximum running speed, and total run time. When a significant age effect was observed, Fisher's post hoc testing was used to determine where significant differences lay between age groups. In all cases, a p value of <.05 was used to determine significance.


   RESULTS
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Body mass (Mb), lean Mb, and the individual mass of the distal hindlimb muscles sampled are shown in Table 2. Total Mb increased from 12 to 24 months, but ultimately decreased by 35 months (p <.05). In contrast, lean Mbwas not significantly different between 12 and 24 months, but also decreased by 35 months (p <.05).


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  		Table 2. Body and Muscle Mass (Mean ± SE).

 
The combined mass of the distal hindlimb muscles sampled (see Table 2) decreased 13% between 12 and 24 months of age, and this accelerated to a 38% decline between 24 and 35 months of age. The overall decline in mass of these distal hindlimb muscles between 12 and 35 months of age was 46%. In contrast to the loss of skeletal muscle mass, there was an age-associated increase in cardiac muscle mass (p <.05, Table 2).

Resting VO2
The average VO2 at rest was 10.9 ± 0.5, 13.2 ± 0.5, and 11.5 ± 0.5 ml O2/min in 12-, 24-, and 35-month-old rats, respectively. When taking differences of Mb into account, ANCOVA revealed no significant differences in resting VO2 among the age groups. In contrast, using lean Mb as a covariate showed significant differences in resting VO2 between 12- and 24-month-old rats.

Maximal VO2 During Exercise (VO2peak)
As expected, VO2peak was decreased with increasing age (ANCOVA, p <.05, Table 3). The average rate of decline in absolute VO2peak was 0.88% and 1.43% per month in 24- and 35-month-old rats, respectively. When accounting for differences in lean Mb (instead of Mb), differences in VO2peak were only observed between 35-month-old rats and the younger 12- and 24-month-old rats (Table 3).


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  		Table 3. ANCOVA of VO2 Data Obtained During Exercise (Mean ± SE).

 
O2 Cost of Exercise
Regression analysis of VO2 (ml/min) against work (i.e., exercise) intensity, excluding resting VO2 data, revealed a linear increase in VO2 in all age groups (Figure 1). Corresponding Pearson's correlation coefficients (r2) are 0.99, 0.99, and 0.91 in 12-, 24-, and 35-month-old rats, respectively.



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  		Figure 1. Graph showing the linear relationships between VO2 (ml/min) and work during exercise, in 12-, 24-, and 35-month-old F344BNF1 rats (n = 20 per age group)

 
When accounting for differences in Mb, ANCOVA revealed that the slope of the relationship between VO2 and work (VO2 slope) tended to increase with age, but this was only marginally significant (p =.07, Table 3). Although a similar trend was also seen using lean Mb, this was not significant (Table 3). Changes in the VO2 intercept, which increased with age, were only statistically significant using absolute VO2 or when lean Mb was used as a covariate (Table 3).


   DISCUSSION
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The results of this study characterize the VO2 response of F344BNF1 hybrid rats to exercise, and for the first time provide VO2 data in senescent rats up to 35 months of age.

It is widely accepted that physical activity (or exercise) is a function of body size (21,22). However, there is considerable debate regarding the mathematical or statistical procedures that should be used to adjust data involving energy expenditure, such as VO2, in order to account for differences in body size (23–26). Assessing VO2 data using the statistical approach of ANCOVA (Table 3) has the advantage of allowing us to statistically account for cofactors (e.g., Mb, lean Mb) that also affect VO2 in addition to the independent variable of interest (i.e., age). Irrespective of the covariate, the slope of the relationship between VO2 and work (VO2 slope) tended to increase with age, but the differences were not significant (Table 3). Only when Mb was used as the covariate did the intercept of the VO2 slope (VO2 intercept) prove not to be significantly different according to age. In the other ANCOVA analyses, the VO2 intercept increased with age (Table 3), which, along with the unchanged VO2 slopes, indicates an age-associated increased O2 cost during physical activity. This is supported by the observation that VO2peak/work increased with age (Table 3), and by previous findings in both mice (14) and man (27) demonstrating a greater O2 cost during exercise with senescence, but is in contrast with data previously found in other rat strains (9,13).

Age-Related Changes in O2 Cost During Exercise
Perhaps the most likely explanation for a greater O2 cost during exercise in senescent rats is a decrease in mechanical efficiency during exercise. Although formal gait analysis was not performed in this study, it was evident that the 35-month-old rats could not move as rapidly and had more difficulty running than younger 12- and 24-month-old animals. Since either increasing or decreasing stride length can alter VO2 (28–30), it is possible that this (or some other change in muscle mechanics) is responsible for increasing the O2 cost during exercise. This is supported by the overall finding that the VO2 intercepts were different between young and older rats (Table 3), with the exception discussed above of Mb used as a covariate. It is also important to note that we do not expect the VO2 intercepts to be the same as resting VO2, since regression analysis (Figure 1) was only performed using data obtained during exercise, thus excluding resting VO2. Accordingly, the VO2 intercepts are not a reflection of resting or basal VO2 but rather represent internal work of exercise. An example of this would be unloaded pedaling on a cycle ergometer, i.e., pedaling against no resistance, whereas, in this study, it is energy required to simply move limbs without performing added external work.

The fact that the O2 cost during exercise was also greater in 24-month-old compared with 12-month-old rats (Figure 1), and no running difficulties were observed in either the 12- or 24-month-old rats, suggests that the increase in O2 cost with exercise is not solely related to mechanical inefficiencies with age. Supporting this, a greater energy cost of walking in healthy 80-year-old subjects compared with 25-year-old subjects was recently reported as not being related to gait instability (31), suggesting the involvement of some other mechanism. Because it is difficult to separate the mechanical effects of walking (or running) from other potential causes that could affect VO2, many investigators prefer to use other exercise modalities, such as cycle ergometry or leg kick, which are not so heavily influenced by Mb and thus reduce the potential of mechanical related inefficiencies. However, such forms of exercise are not feasible in rats.

Since Mb of each animal played a role in determining the absolute work being performed (i.e., heavier rats performed more work than lighter rats), it is possible that the greater relative exercise intensity in the older, heavier rats could result in a nonsteady exercise condition. This would be consistent with the tendency of VO2 slopes to increase with age (Table 3), but again, it is worth noting that the oldest (35-month-old) rats were not the heaviest (Table 2). Therefore, it is unlikely that this could fully explain the age-related difference seen in the O2 cost during exercise.

Age-related muscle atrophy is known to be greatest in the later stages in life and most severe in weight-bearing muscles that have a high proportion of type IIb (fast-twitch glycolytic) fibers (32). Consistent with this, we observed the greatest loss of skeletal muscle mass between 24 and 35 months, with a combined decrease in hindlimb skeletal muscle mass of 38% between 24 to 35 months and only 13% between 12 to 24 months (Table 2). Interestingly, we found that the proportion of type I (slow-twitch oxidative) fibers increased with age, at the expense of type IIb (fast-twitch glycolytic) fibers (15). A similar observation has previously been reported in F344BNF1 rats (33). These findings, however, appear to be at odds with a greater exercise O2 cost in the older rats, since type I fibers are thought to consume O2 more efficiently than type II fibers (34–37). At present, an explanation for this discrepancy is lacking. Fiber type distribution in humans was not found to change between 15 to 83 years of age (38), indicating that it is unlikely that fiber type composition is responsible for increasing the O2 cost during exercise in man. Exceptions to this may involve secondary effects associated with disease, such as chronic obstructive pulmonary disease, where changes in fiber type may in fact play a significant role in increasing O2 cost during exercise (39,40).

Another explanation for a greater O2 cost during exercise in very old rats could involve alterations in mitochondrial efficiency in the handling of O2. In humans, mitochondrial volume density and the oxidative capacity per mitochondrial volume were found to be reduced in elderly subjects (41,42). In our rats, fiber mitochondrial volume density was unchanged between 12 and 35 months of age in the soleus and extensor digitorum longus muscles, i.e., mitochondrial volume per unit fiber length (= fiber cross-sectional area x mitochondrial volume density) decreased in proportion to the fiber atrophy that occurred with age (17). However, a lack of reduction in mitochondrial volume density does not rule out the potential for age-related reduction in mitochondrial oxidative capacity. Hepple and colleagues (43) have found that electron flux through complexes I–III of the electron transport chain was 45% lower in the plantaris muscle of the older (up to 30 months old) F344BNF1 rats compared with younger (8-month-old) F344BNF1 rats. In F344 rats, Lawler and colleagues (44) found that maximal glycolytic flux in the gastrocnemius muscle is adversely affected by acute exhaustive exercise and that this effect is more pronounced with age, but we would anticipated stronger evidence supporting differences in VO2 slope among the age groups, which was not found (Table 3). While a reduced oxidative capacity does not in itself explain a greater age-associated increase in O2 cost during exercise, there is evidence that mitochondria become more leaky to protons with increasing age (45). Thus, a reduced P:O ratio with aging (reduced adenosine triphosphate yield per oxygen molecule) could be expected to contribute to a reduced efficiency of running.

The scope of the current investigation does not allow us to identify the mechanism by which the O2 cost of exercise is greater in older compared to younger rats. We also cannot rule out the possibility that other physiological factors, such as impaired ability to thermoregulate during exercise (46), increased O2 cost of breathing (47,48), and/or a decrease in ventilatory efficiency (49), all of which have also been reported to occur in healthy elderly human subjects during exercise and may also play a role in the greater O2 cost in the older rats during exercise. However, in contrast to our data, it is interesting to note that, in a study where muscle convective O2 delivery was matched between young (8-month-old) and late middle-aged (28–30-month-old) F344BNF1 rats, using an in situ pump-perfused hindlimb preparation, Hepple and colleagues (43) found no significant difference in the O2 cost of contraction across the whole hind limb with aging.

Data Collection and Rat Strain Comparisons
Although many investigators have measured VO2 in rats during exercise, determination of maximal VO2 (VO2max) has always been somewhat difficult in rats, and it is not uncommon to eliminate the poorly performing subjects in an attempt to provide the best characterization of the exercise response. In this study, we chose not to exclude any rats in our analysis. Although, we recognized that this increased the variability in our data, we felt that by not excluding the poorly performing rats, our data would be more representative of each age group's performance. Moreover, this would allow us to assess the potential of phenotypical variation in VO2 among these rats. In this regard, it was not evident that any one age group had more or less poor performers, and given the relatively small coefficient of variation (2%–3%) found among VO2peaks within each respective age group, there does not appear to be significant phenotypic variability. The RER values were not significantly different between age groups (Table 4), and they were similar to those previously reported in other rat strains ranging from 4 to 24 months of age (9–11,13,50). This, and the highly significant linear relationships between VO2 and work in each age group (Pearson's correlation coefficients of 0.99, 0.99, and 0.90 in 12-, 24-, and 35-month-old rats, respectively), gives us confidence in the exercise performance of the rats in each group.


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  		Table 4. Exercise Performance at Peak Exercise (Mean ± SE).

 
One strength of our study is our ability to compare VO2 across all the age groups, since they ran nearly identical exercise protocols (Table 1). Most studies assessing VO2 in rodents have used more simple exercise protocols, where, for example, the incline is set at a fixed level and running speed is increased until VO2peak is achieved. We found that most of the 35-month-old rats were physically unable to move faster than ~8 m/min, in which case VO2 would be limited by mechanical inability to perform the exercise rather than limited aerobic capacity. Therefore, as done in VO2 testing of elderly humans, we chose a protocol that incorporated changes in both incline and speed to reduce the overall maximum speed needed to achieve peak exercise capacity. Compared with 35-month-old rats, the 12- and 24-month-old groups did run a slightly modified protocol during the first few minutes of exercise (Table 1) in order to minimize the total length of time they spent exercising during the test, but all subsequent workloads were identical between age groups, thus giving us the ability to compare O2 utilization among the age groups.

Compared with other rat strains, resting VO2 values in our F344BNF1 rats were consistent with those previously reported in Sprague-Dawley (13,51) and F344 (9) rats up to 24 months of age. However, since we obtained resting VO2 just prior to exercise during a period where the rats were free to move around the metabolic chamber, it may be difficult to compare our resting VO2 data with other measurements of basal or "resting" VO2 in rats. This may explain why, despite significant declines in both lean Mb and skeletal muscle specific mass (Table 2), we did not see an age-associated decline in resting VO2 of our rats, as would be expected in increasing age (52–55).

VO2peak values in 12- and 24-month-old rats were similar to those in other strains at the same age (9–11,13,50,51). Again, a direct comparison of our data to those from other studies may be difficult because the type of exercise and the protocol used directly affect the VO2-to-work relationship (9,50). Moreover, the rats in this study were untrained and not prescreened for their running ability. It is interesting to note, the average rate of decline in specific VO2peak was ~1.5% VO2 ml/min/kg per month in F344BNF1 rats. When taking into account the difference in the life span of a rat compared to a human, this equates to a 7.7% decline per decade, which is close to the 8%–10% decline in VO2max per decade reported in humans (56–58).

Conclusion
These are the first data to characterize whole-body O2 utilization during exercise in F344BNF1 rats and also report VO2 during exercise in very aged rats up to 35 months of age. We found significant declines in VO2peak, and increased O2 cost of exercise with age in F344BNF1 rats. Whether this is due solely, or in part, to mechanical inefficiencies associated with locomotion or to other mechanisms, such as muscle mitochondrial handling of O2, remains to be determined.


   Acknowledgments
 
Funding support for this study was provided by NIH HL17731, HL07212, and MO1 RR00827.

The authors wish to express their appreciation to Jeff Struthers and Nick Busan for their technical assistance; Dr. Elizabeth Barrett-Conner and Diane Clafin, CRT, for the use of the DEXA scanner and assistance in measuring body composition; Dr. Susan Hopkins and Dr. Russ Richardson for their advice; and Dr. Reena Deutsch and Feng He for statistical advice.


   Footnotes
 
Decision Editor: Edward J. Masoro, PhD

Received September 9, 2003

Accepted May 4, 2004


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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